FI95252B - Process for the preparation of dihydrotianaphthalene compounds useful as a drug - Google Patents

Abstract

Compounds of formula (I): <CHEM> (wherein n is 0 or 1, R<1> and R<2> are hydrogen or alkyl, one of A<1> and A<2> is - Z-Y and the other is-W-COOH, where W and Z are alkenylene or alkylene and Y is imidazolyl or pyridyl, and the broken lines represent two single bonds or one single bond and one double bond) and their salts, esters and amides have the ability to inhibit the synthesis of thromboxane A2 and hence are useful in the treatment or prophylaxis of thrombotic conditions. They may be prepared by introducing an imidazolyl or pyridyl group into the corresponding compound in which Y is replaced by an active group or atom.

Description

952E2

Process for the preparation of dihydrothianaphthalene compounds useful as medicaments For the preparation of dihydrothianaphthalene compounds which can be used as medicaments 5

The invention relates to a process for the preparation of dihydrothianaphthalene compounds of the formula (I) which can be used as medicaments: in one of the groups A1 and A2 represents a group of the formula -ZY, in which Y represents an imidazolyl or pyridyl group and Z represents a methylene- , an ethylene, trimethylene or vinylene group or a methylene, ethylene, trimethylene or vinylene group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl groups, C 3 -C 6. cycloalkyl groups, phenyl or naphthyl groups, substituted phenyl groups having at least one substituent selected from the group consisting of C1-C * alkyl groups, C1-C * alkoxy groups, halogen atoms, nitro groups, cyano groups and amino groups; and thienyl groups; One of A1 and A2 represents a group of the formula -W-COOH, wherein * W represents a direct bond, a methylene group, a methine group, provided that W represents only said methine group when A1 represents said group of the formula -Z-Y; A2 is in the 5- or 6-position of the thianaphthene system; 2 9E252 Each dashed line represents a single or double carbon-carbon bond between the 4- and 5- or 6- and 7-arms, provided that when A2 is in the 5-position there is a single bond between the 6- and 7-positions and that when A2 is 6- the position between positions 4 and 5 has a simple bond; 5 and pharmaceutically acceptable salts, amides and esters thereof.

The present invention relates to a series of thianaphthene derivatives which have been found to have certain valuable therapeutic properties.

The compounds of the invention have the ability to inhibit platelet aggregation and biosynthesis of thromboxane A2 (hereinafter conventionally referred to as nTXA2M).

15

The compounds of the present invention can be considered as thianaphthene derivatives [The Merck Index, 10th Edition (1983) monograph 9142] having the formula (A):

Il (A)

A

Ί / 25

The compounds of the present invention are named semi-systematically with thianaphthene as the parent compound in accordance with the recommendations of the International Union of Pure and Applied Chemistry, Commission on Nomenclature of Organic Chemistry. For the avoidance of doubt, the ‘numbering system’ used herein is used in formula (A) above.

TXA2 plays a significant role in the formation of platelet aggregation and inhibition of its biosynthesis is believed to reduce the amount of platelet aggregation, not to mention the direct effect these compounds may have on such aggregation. It is known that TXA2 is formed from endoperoxide PGH2 via PGG2. It is known that the activity of TXA2 3 95252 is generally opposite to the activity of PGI2, which causes an increase in vasodilation and inhibits platelet aggregation. Accordingly, it has been suggested that the balance between TXA2 and PGI2 in the blood is a dominant factor in the development and / or improvement of vascular occlusion. Thus, for thrombus treatment or treatment, it is desirable to selectively inhibit TXA2 biosynthesis and thus promote PGI2 activity (which has an inhibitory effect on platelet aggregation) and also to increase PGI2 levels as a result of PGH2 accumulation.

10 A potent inhibitor of TXA2 biosynthesis is believed to be of considerable value in the treatment or treatment of a wide variety of diseases and disorders associated with the circulatory system. However, it is important that this inhibitory activity does not result in inhibition of the enzymes responsible for the synthesis of other prostaglandins.

15

Various compounds have been proposed for such use. According to one proposal, it has been proposed to use certain thianaphthene derivatives for this purpose and the compounds disclosed in EP 73663 B1 have the necessary activity.

20

We have now found that certain thianaphthenes in which the 6-membered ring is partially saturated have a considerable ability to inhibit TXA2 synthesis, which is an order of magnitude or more orders of magnitude better than the known compounds currently available for this purpose. Although the compounds of EP 73663 B1 are seemingly similar to the compounds of the invention, they have a fully saturated and aromatized thianaphthene ring system. In contrast, the compounds of the invention have a partially saturated 6-membered ring. The aromaticity of the prior art compounds results in the rigidity of the molecular structure and configuration and the fluidity of the electron stream that the compounds of the present invention do not possess and could be expected to have a substantial effect on the biological properties of the compounds. It is therefore surprising that the compounds of the invention have biological properties similar in nature to those of the prior art, especially since the activity in question is related to the activity of enzymes, where differences between the prior art and the compounds of the invention would be expected to have a significant effect.

95252 4

The invention further provides a pharmaceutical composition comprising an inhibitor of TXA2 biosynthesis in admixture with a pharmaceutically acceptable carrier or diluent, said inhibitor being selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable esters, amides and salts thereof.

The invention further provides a method of treating or treating a disease or disorder resulting from an imbalance in TXA2 levels in an animal, a normal mammal, including a human, comprising administering to said animal an effective amount of an inhibitor of TXA2 biosynthesis, said inhibitor being selected. from the group consisting of compounds of formula (I) and pharmaceutically acceptable esters, amides and salts thereof.

When the carboxy group is esterified, the quality of the resulting ester is not critical to the present invention. In principle, the compounds of the invention, being carboxylic acids, may form esters with any ester-forming alcohol, and all such esters form part of the present invention. However, when the esters are to be used for therapeutic purposes, it is, of course, necessary that the resulting esters be pharmaceutically acceptable, which means, as is known in the art, that the esters should not have reduced activity (or undesirably reduced activity) and should not have increased toxicity (or undesirably increased toxicity) compared to the free acid.

However, when the ester is to be used for other purposes, for example as an intermediate in the preparation of other compounds, this criterion also does not apply.

Examples of such esters include: C 1 -C 6, preferably C 1 -C 4 alkyl esters, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and hexyl esters; aralkyl and diaralkyl esters such as benzyl, N-nitrobenzyl and benzhydryl esters; alkoxycarbonylalkyl esters in which the alkoxy and alkyl moieties are both C 1 -C 4, especially alkoxycarbonylmethyl esters such as ethoxycarbonylmethyl and t-butoxycarbonylmethyl esters; alkoxycarbonyloxyalkyl esters in which the 5 95252 alkoxy and alkyl moieties are both C 1 -C 3, especially 2- (alkoxycarbonyloxy) ethyl esters such as 2-methoxycarbonyloxyethyl, 2-ethoxycarbonyloxyethyl and 2-t-butoxycarbonyloxyethyl esters; and other specific esters such as phthalidyl, substituted phthalidyl, phenazyl, substituted phenacyl (e.g. p-nitrophenyl) and (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esters.

Similarly, when one or more carboxy groups form an amide, the exact quality of the amide is not critical, provided that when the amide is to be used for therapeutic purposes, the resulting amide is pharmaceutically acceptable. Accordingly, one or more of these carboxy groups may be replaced by a carbamoyl group or a substituted carbamoyl group, preferably an alkylcarbamoyl or dialkylcarbamoyl group, wherein the alkyl group or each alkyl group is a C 1 -C 3 alkyl group, for example methylcarbamoyl or dimethylcarbamoyl, ethylcarbamoyl, ethylcarbamoyl.

One or more of these carboxy groups may also form salts with suitable acids. In addition, because the imidazolyl and pyridyl nitrogen atoms are basic in nature, the compounds of the invention may also form acid addition salts. The quality of such salts is also not critical, provided that when they are to be used for therapeutic purposes, the salts are pharmaceutically acceptable. A wide variety of acids can form acid addition salts with the compounds of the invention, and examples of such acids include: mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and phosphoric acid; organic carboxylic acids such as acetic acid, trifluoroacetic acid, aspartic acid, glutamic acid, oxalic acid, tartaric acid, citric acid, maleic acid, fumaric acid, lactic acid, salicylic acid, malonic acid and succinic acid; and organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and n-toluenesulfonic acid ·

Examples of salts with bases include: salts with metals, especially alkali metals and alkaline earth metals, such as lithium, sodium, potassium, calcium and magnesium salts; ammonium salt; salts with organic amines such as cyclohexylamine, diisopropyl-952526 amine or triethylamine; and salts with basic amino acids such as lysine or arginine.

The compounds of the invention may contain several asymmetric carbon atoms and accordingly optical isomers of the compounds are possible. Although various optical isomers are all represented herein by a single formula, the present invention encompasses both the individual isolated isomers and mixtures thereof.

The most preferred compounds of the invention are: 4,5,6,7-tetrahydro-2- (1-imidazolyl) methylthianaphthene-6-carboxylic acid and 4,5-dihydro-2- (1-imidazolyl) methylthianaphthene-6 carboxylic acid.

Also preferred are pharmaceutically acceptable salts, esters and amides of the above compounds, especially salts and esters, especially alkali metal salts (especially sodium) and lower alkyl esters (especially methyl).

The process according to the invention is characterized in that a compound of formula (II) is administered: wherein the dashed lines are as defined above; one of the groups B1 and B2 represents a group of the formula -WC00H represented by Ax or Az or - 7 95252 groups in which the carboxy group is protected, and one of the groups B1 and B2 represents a reactive group such as a hydroxy, halogen, lower alkanesulfonyloxy or arylsulfonyloxy group or is a carbonyl derivative of a group Z in which Z is as defined above) to react with an imidazolyl group. or a pyridyl compound to introduce an imidazolyl or pyridyl group represented by Y into said compound and, if necessary, subjecting the resulting compound to reduction and / or hydrolysis and / or deprotection, and if desired the salts are prepared by known methods, preferably by contacting with a suitable acid or base. with.

In more detail, the compounds of the invention may be prepared as described in any of the following methods A-F.

15 Method A

In this method, a compound of formula (Ia): wherein R 1 is H, R 2 is H and n is 1 and the dashed lines are as defined above; Y1 represents an imidazolyl group; and Z 1 represents a methylene, ethylene or trimethylene group which is unsubstituted or has at least one substituent selected from the group consisting of substituents (b) as defined above; wherein the group 35 of said formula -Z1-Y1 is at any of the 2-, 5- and 6-positions of the thianaphthene system and the group of said formula -W-C00H is at any of said 2-, 8-position or 6-positions of the formula -Z1-Y1 compound], namely a compound of formula (Ial): | (lal) 10 compound of formula (Ia2): 15 a '\ ___' W-cooh j-1 (Ia2) 2o or compound of formula (Ia3): · „, | | __2 ^ -Y '(Ia3)

HD0C-W S

30 (wherein R 1, R 2, n, W, Y 1, Z 1 and the dashed lines and dotted lines are as defined above) can be prepared by reacting a compound of formula (III):

II

9 95252 L 1, J <m> x-ζ1 ^^ ^ '' ^ w-ctum3 10 (wherein R1, R2, W, n, Z1 and the dashed lines are as defined above; R3 represents a carboxy protecting group; and X represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group wherein said -Z1-X group is at any of the 2-, 5- and 6-positions of the thianaphthene system and said -W-COOR3 group of said formula is at any of said 2-, 5- and 6-positions having no said group of formula -Z1-X) to react with a compound of formula (IV): Y: H (IV) 2 O (wherein Y1 is as defined above), i.e. imidazole, or an alkali metal salt thereof (e.g. lithium, sodium or potassium salt) and, if necessary, hydrolysing the resulting compound.

In formulas (II), (Ia) and (III) above, the charges which are relative to A2 in the compounds of formula (I) apply mutatis mutandis to the corresponding group B2, -Z1-Y1, -W-C00H, -Z1- X or -W-C00R3, namely when in the 5-position the single bond should be between the 6- and 7-positions and when in the 6-position the single bond should be between the A- and 5-positions. The same is true for the corresponding formulas given later.

When X represents a halogen atom, this is preferably a chlorine, bromine or iodine atom. When X represents a lower alkanesulfonyloxy group, this is preferably a C 1 -C * alkanesulfonyloxy group, for example a methanesulfonyloxy or ethanesulfonyloxy group. When X represents an arylsulfonyloxy group, preferred such arylsulfonyloxy groups include benzenesulfonyloxy and n-toluenesulfonyloxy groups.

When the carboxy group in the group -W-C00H is protected, it is preferably protected by conversion to an ester group, especially a lower alkyl ester, and R3 is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t -butyyliryhmä.

The reaction between the compound of formula (III) and the compound of formula (IV) is preferably carried out in the presence of a solvent, the quality of which is not critical, provided that it does not adversely affect the reaction. Examples of suitable solvents include: halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; alcohols such as methanol, ethanol or t-butanol; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile; and lower aliphatic acid amides such as dimethylformamide.

The reaction takes place over a wide range of temperatures, and the particular temperature selected is not critical to the invention. However, in general, we have found it convenient to carry out the reaction at a temperature in the range from 10 ° C to the boiling point of the solvent used. The time required for the reaction will vary widely depending on many factors, notably the nature of the reagents and the reaction temperature; however, a temperature of 1 to 20 hours will normally suffice at a temperature of 25 in the recommended range.

When the resulting compound is to be hydrolyzed, it can be obtained in a conventional manner by contacting the ester obtained in the above reaction with a hydrolyzing agent which may be an acid or a base. There is no particular restriction on the nature of the acid or base to be used as a hydrolyzing agent, and any such compound commonly used for hydrolysis can be used in the present reaction. However, examples of suitable hydrolysing agents include: mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; and alkali metal hydroxides such as sodium hydroxide or potassium hydroxide.

II

11 95252

The reaction is normally carried out in the presence of a solvent, the quality of which is not critical, provided that it has no adverse effect on the reaction. In general, we recommend the use of an alcohol such as methanol or ethanol or a mixture of such alcohol and water as the solvent.

5

The reaction takes place over a wide range of temperatures, and there is no particular restriction on the exact temperature used. In general, we have found it convenient to carry out the reaction at a temperature in the range of from room temperature to 110 ° C. The time required for the reaction may vary widely, depending on many factors, notably the reaction temperature and the nature of the hydrolysing agent employed. However, at the temperatures proposed above, a time of 10 minutes to 6 hours is normally sufficient.

When the reaction is complete, the desired product can be recovered from the reaction mixture by conventional recovery techniques and then, if necessary, further purified by conventional techniques such as recrystallization, distillation or various chromatographic techniques, especially column chromatography.

20 Method B

The thianaphthene compounds of formula (Ia) as defined in Method A above may also be prepared by reacting a compound of formula (V): i TJ <v) H0-Z, /> <S '^' ^ VV-CflOR3 (where R1 , R 2, R 3, W, Z 1, n and the dashed lines are as defined above, wherein the -Z 1 -HH group of said formula is at any of the 2-, 5- and 6-positions of the thianaphthene system and the -W-COOR 3 group of said formula is wherein any of said 2-, 5- and 6-positions without said -Z1-OH group of formula) to react with a thionyldiimidazole compound of formula (VI): 12 95252 Y1-S (= O) -Y1. (VI) (wherein Y 1 is as defined above) and, if necessary, hydrolyzing the resulting compound.

5

As described in Method A, the charges associated with A2 apply mutatis mutandis regardless of which of the groups -Z1-OH and -W-COOR3 is in the 5- or 6-position.

The reaction of a compound of formula (V) with a thionyldiimidazole compound of formula (VI) is preferably carried out in the presence of a solvent of non-critical quality, provided that it does not adversely affect the reaction. Examples of suitable solvents include: halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons such as methylene chloride or chloroform; ethers such as diethyl ether, tetrahydrofuran or dioxane; and aromatic hydrocarbons such as benzene, toluene or xylene. Although not essential, the reaction is aided by carrying it out in the presence of a base, preferably an organic base, and more preferably a tertiary amine such as 4-dimethylaminopyridine.

The reaction takes place over a wide range of temperatures, and there is no particular restriction on the particular temperature selected. In general, we have found it convenient to carry out the reaction at a temperature in the range of from 0 ° C to the boiling point of the solvent used. The time required for the reaction may vary widely, depending on many factors, notably the nature of the reagents and the reaction temperature. However, at a temperature in the range suggested above, a time of 1 minute to 12 hours is normally sufficient.

When the reaction is complete, the reaction mixture is preferably poured into water and then treated in a conventional manner to recover the desired compound. If necessary, this can be further purified in a conventional manner, for example by recrystallization, distillation or various chromatographic techniques, in particular column chromatography. 35 ft 11 13 95252

If hydrolysis is required, it can be performed before or after recovery and / or purification by the conventional method described in Method A.

5 Method C

Compounds of formula (Ie): io j '(Ie)

y2_2 W-CQQH

15 (wherein R 1, R 2, W, Z, n and the dashed lines are as defined above; and Y 2 represents a pyridyl group; said formula -Z-Y 2 being at any of the 2-, 5- and 6-positions of the thianaphthene system and said formula 20 -W When the -COOH group is at any of said 2-, 5- and 6-positions without said group -Z-Y2) can be prepared by reacting a compound of formula (VII): n>> (VII) lv

L / C- (CH2l „r S # -CDQÄJ

[Wherein R 1, R 2, R 3, W, n and the dashed lines are as defined above; R 4 represents a hydrogen atom or any of the groups defined as substituents (b), namely a C 1 -C 3 alkyl group, a C 3 -C 6 cycloalkyl group, a C 6 -C 10 aryl group, a substituted C 6 -C 10 aryl group having at least one of the substituents (a) or a heterocyclic group; and m represents the number 0 or the integer 1 or 2; wherein the group of said formula 14 95252 - (CH2) mC (= O) -R * is at any of the 2-, 5- and 6-positions of the thianaphthene system and the group of said formula -W-COOR3 is at any of said 2-, 5- and 6- from positions without said group of the formula - (CH 2) m C (= O) -R *] to react with a lithium compound of formula 5 (VIII):

Y 2 -L 1 (where Y 2 is as defined above), by reducing or dehydrating the resulting compound and then, if necessary, hydrolyzing the compound thus obtained.

The first step of this reaction, namely the reaction of a compound of formula (VII) with a lithium compound of formula (VIII), converts a group of formula 15 - (0112), -O (-O) -R * in a compound of formula (VII) to a group of formula:

OH

| (B) 20 -ICtym-C-n '* Y2

(wherein m, Y 2 and R * are as defined above). This reaction is preferably carried out in the presence of a solvent, the quality of which is not critical, provided that it has no adverse effect on the reaction. Suitable solvents include ethers, especially diethyl ether or tetrahydrofuran. The reaction will take place over a wide range of temperatures, and the precise temperature selected will not be critical.

- +30 ° C. The time required for the reaction varies widely, depending on many factors, notably the reaction temperature and the nature of the reagents; however, at a temperature within the proposed range, a time of 30 minutes to 5 hours will normally suffice.

When the reaction is completed, the excess lithium compound (VII) is decomposed, e.g. by adding water or, preferably, an aqueous solution of a salt, especially an ammonium salt of ammonium such as ammonium chloride. The reaction mixture is then preferably treated in a conventional manner to recover the desired compound containing the above-mentioned group of formula (B), and then the resulting compound can, if desired, be further purified by a conventional method such as recrystallization, distillation or various chromatographic techniques, especially column chromatography.

In the next step of the reaction, a compound containing a group of formula (B) as defined above is reduced. The reduction is preferably carried out with hydrogen 10 in the presence of a catalyst such as palladium on carbon or platinum oxide. The reaction is preferably carried out in the presence of a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid. The reaction is preferably carried out in the presence of a solvent of non-critical quality, provided that it has no adverse effect on the reaction.

Examples of suitable solvents include: esters such as ethyl acetate: aromatic hydrocarbons such as benzene or toluene; and alcohols such as methanol or ethanol. When the reaction is completed, the resulting product can be recovered from the reaction mixture by conventional means to give a compound of formula (Ie) wherein Z represents a methylene, ethylene or trimethylene group which is unsubstituted or has one or more of the substituents (b).

When m represents an integer of 1, the resulting compound can be dehydrated to give a compound of formula (1c) wherein Z represents a vinylene group. This reaction is preferably carried out in the presence of an organic solvent, the quality of which is not critical, provided that it has no adverse effect on the reaction. Examples of suitable solvents include: aromatic hydrocarbons such as benzene, toluene or xylene; and ethers such as dioxane or tetrahydrofuran. The dehydration reaction is preferably carried out by adding a catalytic amount of a strong acid, for example an organic sulphonic acid such as β-toluenesulphonic acid or a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid. The water formed in the reaction is removed, preferably during the reaction, to assist in the completion of the reaction, and preferably by azeotropic distillation with heating.

16 · 16 95252

If necessary, the product is then subjected to hydrolysis as described in Method A. When the reaction is complete, the desired product can be recovered from the reaction mixture by conventional means to give a compound of formula (Ie) wherein Z represents a vinylene group which may be unsubstituted or may have at least one of the substituents (b).

If necessary, the compound prepared as described above can be further purified by conventional techniques such as back-sintering or various chromatographic techniques, especially column chromatography.

Method D

15 Compounds of formula (Id): L,.-V ’"

20 | I

I 11 J <I4)

y1_22 '> <S W-C00H

[Wherein R 1, R 2, W, Y 1, n and the dashed lines are as defined above; and Z2 represents a vinylene group or a vinylene group having at least one of the substituents (b) defined above, namely an alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group * 'or a heterocyclic group; wherein said group of formula -Z2-Y1 is at any of the 2-, 5- and 6-positions of the thianaphthene system and said group of formula -W-C00H is at any of said 2-, 5- and 6-positions without said group of formula -Z2- Y1 group] can be prepared by reacting a compound of formula (VIII): l 17 95252 r1x ^ - <m (rZ | "5 (VIII) ° ^ C-CH, S" W-COOR3 10 [wherein R1, R 2, R 3, R 4, W, n and the dashed lines are as defined above, wherein the group -CH 2 -C (= O) -R 4 of said formula is at any of the 2-, 5- and 6-positions of the thia-naphthenic system and -W -COOR 3 having 15 groups at any of said 2-, 5- and 6-positions without said group of formula -CH 2 -C (-O) -R 4], namely a compound of formula (VII) (see Method C) wherein m is 1, to react with a thionyldiimidazole compound of formula (VI): Y-SC-OJ-Y1 (VI) (wherein Y1 is as defined above - see Method B) and, if necessary, hydrolyzing the resulting compound.

The reaction of these compounds can be carried out using the same reaction conditions and work-up as described in Method B.

Method E

30 Tianaphthene derivative of formula (Ie): R '/ W' "'2'» 35 <Ie>

YLZ3> S ^ KW_C0DH

• 95252 18 [wherein R 1, R 2, W, Y 1, n and the dashed lines are as defined above; and Z 3 represents an ethylene, trimethylene or vinylene group or a group having at least one substituent selected from the group consisting of substituents (b), namely alkyl, cycloalkyl, substituted and unsubstituted aryl and heterocyclic groups as defined above; wherein said group of formula -Z 3 -Y 1 is at any of the 2-, 5- and 6-positions of the thia-naphthenic system and said group of formula -W-COOH is at any of said 2-, 5- and 6-positions without said group of formula - Z3-Y1] can be prepared by reacting a compound of formula (IX): R'v1 ^) <'R2 | n

15 I

J (CHI 3 Y HCH 2) p -C W-C00R 3 [wherein R 1, R 2, R 3, Y 1, W, n and the dashed lines are as defined above; and £ is 1 or 2; wherein the group of the formula -C (-O) - (CH2) p-Y1 is at any of the 2-, 5- and 6-positions of the thianaphthene system and the group of said formula -W-C00R3 is at any of said 2-, 5- and 6-positions. -25 positions without said group of formula -C (-O) - (CH 2) p -Y 1] to react with a reducing agent or an organolithium compound of formula (X): R 5 Li (X) 30 or a Grignard reagent having has the formula (XI): R 5 MgX '(XI) 35 [wherein R 5 represents any of the groups defined above as substituents (B), namely a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group, a C 6 -C 10 aryl group, a substituted C 6 -C 10 aryl group or a heterocycle n 19 95252 group; and X 'represents a halogen atom, for example a chlorine, bromine or iodine atom] to give a compound of formula (XII):

R1> -r ^ 1 <R2ln OH L. JL (XII) .C W-C00R3 10 1 / \ / r- (CH2) p Ru [where R1, R2, R3, W, Y1, n, e and the dashed lines are as defined above; wherein the group of said formula - (OH) C (RA) - (CH 2j-Y 1) is at any of the 2-, 5- and 6-positions of the thianaphthene system and the group of said formula -W-CO 2 R 3 is in any of said 2-, 5- and 6-position positions without said - (OH) C (RA) - (CH2) p-Y1 group] and then reducing and / or dehydrating said compound of formula (XII) and, if necessary, hydrolysing the resulting product.

When the compound of formula (IX) is reacted with a reducing agent in the first step of this reaction, the reducing agent is preferably a metal. a hydride such as sodium borohydride or sodium cyanoborohydride. Reaction 25 is preferably carried out in the presence of a solvent of non-critical quality provided that it does not adversely affect the reaction. Suitable solvents include, for example: ethers such as diethyl ether or tetrahydrofuran; and alcohols such as methanol. The reaction takes place over a wide range of temperatures, and the particular temperature selected is not critical to the invention. In general, we have found it convenient to carry out the reaction at a temperature in the range of from 0 ° C to the boiling point of the solvent used. The time required for the reaction will vary widely depending on many factors, notably the nature of the reagents and the reaction temperature; however, at a temperature within the recommended range, a time of 30 minutes to 5 hours will normally suffice. When the reaction is complete, the reaction mixture can be worked up by conventional means to recover the desired product, after which the product, 95252 20 compound of formula (XII), can be further purified by conventional techniques such as recrystallization, distillation or various chromatographic techniques, especially column chromatography.

Alternatively, in the first step of the reaction, the compound of formula (IX) may be reacted with an organolithium compound of formula (X). This reaction is preferably carried out in the presence of a solvent of non-critical quality, provided that it has no adverse effect on the reaction. Suitable solvents include ethers such as diethyl ether or tetrahydrofuran. The reaction takes place over a wide range of temperatures, and the precise temperature selected is not critical to the invention. In general, we have found it convenient to carry out the reaction at a temperature in the range of -73 ° C to + 30 ° C. The time required for the reaction may vary widely, depending on many factors, notably the nature of the reagents and the reaction temperature; however, at a temperature within the recommended range, a time of 30 minutes to 5 hours will normally suffice. When the reaction is completed, it is recommended to decompose the excess organometallic compound by adding water or, preferably, an aqueous solution of a salt, especially an ammonium salt such as ammonium chloride, to the reaction mixture. The mixture can then be treated by conventional techniques to recover the desired compound of formula (XII), which can then be further purified, if necessary, by conventional techniques such as distillation, recrystallization or various chromatographic techniques, especially column chromatography.

25

Alternatively, a compound of formula (IX) may be reacted with a Grignard reagent of formula (XI). This reaction is preferably carried out in the presence of a non-critical solvent, provided that it has no adverse effect on the reaction and is substantially inert to the Grignard reagent; examples of suitable solvents are ethers such as diethyl ether and tetrahydrofuran. The reaction takes place over a wide range of temperatures, and the particular temperature selected is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature in the range of 35 ° C to the boiling point of the solvent employed. The time required for the reaction may vary widely, depending on many factors, notably the nature of the reagents and the reaction temperature; however, at temperatures within the recommended range, a time of 30 minutes to 10 hours will normally suffice. When the reaction is complete, it is recommended to decompose the excess Grignard reagent (XI) by adding 5 water or, preferably, an aqueous solution of a salt, especially an ammonium salt or ammonium chloride. The reaction mixture can then be treated by conventional means to recover the desired compound of formula (XII), which can then, if necessary, be further purified by conventional techniques such as distillation, recrystallization or various chromatographic techniques, especially column chromatography.

The resulting compound of formula (XII), regardless of how it is prepared, is then subjected to reduction and / or dehydration. If desired, the compound of formula (XII) may then be subjected to the same reduction or dehydration reactions as described in connection with Method C. However, a more preferred reaction sequence is as follows.

First, the compound of formula (XII) is reacted with an alkali metal hydride, for example sodium hydride, by mixing the compound with the hydride, preferably in the presence of a suitable solvent. The quality of the solvent is not critical provided that it has no adverse effect on the reaction. Suitable solvents include: ethers such as diethyl ether or tetrahydrofuran; and aromatic hydrocarbons such as benzene or toluene. The reaction temperature is not critical and we have generally found it convenient to carry out the reaction at a temperature in the range of 0 ° C to the boiling point of the solvent used. Carbon disulfide and a lower alkyl halide, for example a methyl halide such as methyl iodide, are then added. These are then reacted to give a compound of formula (XIII): 30 K1 gi / S. • W-COOR3 i / \ n αΐΙΠ Y3 - [CH2 lp / \ s S S-R6 22 95252 [wherein R 1, R 2, R 3, R 1, W, Y 1, n, g and the dashed lines are as defined above; and R6 represents a lower alkyl group, preferably a methyl group; each of the groups -W-COOR3 and - (R1) C (OCS2R6) - (CH2) p-Y1 in any of the 2-, 5- and 6-positions of the thianaphthene system, provided that they are not both in the same position]. The reaction takes place over a wide range of temperatures, and the particular temperature selected is not particularly critical; in general, we have found it convenient to carry out the reaction at a temperature in the range of 0 ° C to the boiling point of the solvent used. The time required for the reaction may vary widely depending on the nature of the reagents and the reaction temperature; however, at a temperature within the proposed range, a time of 10 minutes to 1 hour will normally suffice. The reaction is preferably carried out in the same reaction medium used for the reaction with the alkali metal hydride.

The resulting compound is then preferably reduced with tributyltin hydride or dehydrated and, if necessary, hydrolysed to give the desired compound of formula (Ie).

The free radical reduction of the compound of formula (XIII) with dibutyltin hydride 20 is preferably carried out in the presence of an organic solvent, the quality of which is not critical, provided that it does not interfere with the reaction. Examples of suitable solvents include: ethers such as diethyl ether or tetrahydrofuran; and aromatic hydrocarbons such as benzene or toluene; one or a mixture of two or more of these solvents may be used. The reaction is also preferably carried out in the presence of α, α1 -azobisisobutyronitrile. The reaction is preferably carried out under heating, suitably at reflux, to give the desired compound of formula (Ie) in which Z represents an ethylene or trimethylene group which is unsubstituted or in which at least one of the substituents (b) is present. The time required for the reaction can vary widely depending on many factors, in particular the reaction temperature; but normally sufficient time is 10-30 hours.

Alternatively, the compound of formula (XIII) may be dehydrated. This is preferably done by adding a catalytic amount of a strong acid, for example an organic sulphonic acid such as p-toluenesulphonic acid or a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid. Reaction ti 23 95252 is preferably carried out in the presence of an organic solvent, the quality of which is not critical, provided that it does not interfere with the reaction. Suitable solvents include, for example: aromatic hydrocarbons such as benzene, toluene or xylene; and ethers such as dioxane or tetrahydrofuran. The water formed in the reaction is preferably removed during the reaction to assist in the completion of the reaction. The removal of water is preferably carried out by azeotropic distillation. The resulting compound is a compound of formula (Ie) wherein Z represents a vinylene group which is unsubstituted or has at least one of the substituents (b).

10

If necessary, the resulting compound can be subjected to hydrolysis as described in connection with Method A.

The resulting compounds can be separated from their corresponding reaction mixtures by conventional means and, if necessary, further purified by conventional techniques such as recrystallization or various chromatographic techniques, especially column chromatography.

Method F

20

Tetrahydrothianaphthene derivatives of formula (If): 1 25 e \ I I CIf)

v-z s caoH

30 (wherein R 1, R 2, W, Y, Z and n are as defined above; each of said groups of the formula -ZY and -W-C 10 H are in any of the 2-, 5- and 6-positions, provided they are not both in the same position), 35 can be prepared from the corresponding dihydrothianaphthene derivative (namely having a double bond between the 4- and 5- or 6- and 7-positions) in a reduction manner by hydrogenation. The starting material can be prepared by any of the above methods A-E.

The reduction process is preferably carried out in the presence of a solvent, the quality of which is not critical, provided that it has no adverse effect on the reaction. Examples of suitable solvents include: esters such as ethyl acetate; aromatic hydrocarbons such as benzene or toluene; alcohols such as methanol or ethanol; and ethers such as tetrahydrofuran or dioxane. The reaction takes place in the presence of hydrogen and a catalyst, preferably palladium on carbon or platinum oxide.

When the reaction is complete, the resulting product can be recovered from the reaction mixture by conventional means and, if necessary, it can be subjected to hydrolysis before or after recovery as described in Method A. If desired, the product of formula (If) can be further purified by conventional techniques such as distillation, recrystallization or various chromatographic techniques, especially column chromatography.

The starting materials used in the above processes can be prepared by a variety of methods known in the art for the preparation of this type of compound. The following methods G-P can be used as an example.

Method G In this method, the starting materials of formulas (III), (V) and (VII) wherein Z represents an optionally substituted methylene group, W represents a direct bond and the group -W-C00R3 is in the 5- or 6-position, namely formulas (IIIa), Compounds (Va) and (Vila) can be prepared as shown in the following reaction schemes: * <il 25 95252 Γ-CO (087); Π-NaBHi, S-V “''« 'Vw Q ((XIY1 (XY) «2CMCH3] ill /> - TsOHr Π II” RSC0Ct' S ^ J ^ COOR7 S ^^^ ITOOR7 3

OH

(XVI) (XVIII

I-jf ^ l Π ij ^ <R ^ -C ^ '' ^^^^ COOR7 R4-CH S ^^^^ IQOH7% \ h (Vila) (Yal -s * - χιΠ —CH $ COOR? (Ilia ) * 95252 26

In the above formulas, R * 1 is as defined above; R7 represents a carboxy protecting group (e.g. as shown in connection with the group R3 as defined above); and Re represents an alkyl group, a cycloalkyl group or a substituted or unsubstituted aryl group as defined in connection with the corresponding groups referred to in the substituents (b).

Corresponding compounds of formulas (VIIIb), (IIIb) and (IIIb): 10cOOfl7 15 cviib) \ 20 coon? (Vb)

R-CH S

\ (iiib)

OH

25

, jcC

ir-cr s ^ \ 27 95252 (wherein Ra, R7 and X are as defined above), namely the group -COOR7 at the 5-position, can be prepared with exactly the same reaction sequence as described above but starting with compound (XIVa): 50 , _ | | (XIVa) instead of 10 a compound of formula (XIV).

In the first step of this reaction, the starting material of formula (XIV) [or (XIVa)] is reacted with a dialkyl carbonate of formula CO (OR7) 2 in the presence of a metal hydride, for example sodium hydride, to give a compound of formula (XV). This is then reacted with a reducing agent, for example sodium borohydride, to reduce the ketone oxygen to the hydroxy group in the compound of formula (XVI). This is then reacted with a dehydrating agent, for example j-toluenesulphonic acid (p-TsOH), preferably at reflux and preferably in solution, for example in benzene, to give the compound of formula (XVII). This is then subjected to a Friedel-Crafts reaction with a compound of formula CL2CH0CH3 or R8COCl in the presence of aluminum chloride to give the acyl compound (VIIa) [or (VIIb)]. If desired, this can be reduced, for example with sodium borohydride, to give the corresponding alcohol (Va) [or (Vb)] and again, if desired, this can be halogenated or sulfonylated by conventional means to give a halogen or sulfonyl derivative of formula (IIIa) [or (IIIb)].

30

Method H

The starting materials of the formulas (III) and (V) in which Z1 represents an optionally substituted ethylene group and the group -COOR7 is in the 5- or 6-position, namely the compounds of the formulas (IIIc) and (Vc), and the compounds of the formula (VII) in which in is 1, R 4 is a hydrogen atom, W represents a direct bond and 95252 The group COOR 3 is in the 5- or 6-position, namely the compounds of formula (VId), can be prepared as described in the following reaction schemes: 29 95252 li-f ^ -coni ΞΕϊΑίΙ® ^ Λ -SuLi 0 (Ylle) n-7 HC £ I | --COOR7 - cw Ji, (XVIII] n-7 Na% H - COOR7 - = - (Ylldl I j £ ^ j — COOR7 HX —- R1 * (Vc) (III e) 30 95252

In the above formulas, R * 1, R 7 and X are as defined above; the group -C00R7 is in the 5- or 6-position: and the dotted lines mean that when -C00R7 is in the 5-position, the double bond is between the 4- and 5-positions and the single bond is between the 6- and 7-positions, and when -COOR7 is in the 6-5 position, the double bond is between the 6- and 7-positions, and the single bond is between the 4- and 5-positions.

In the first step of this reaction, a compound of formula (VIIc) [namely a compound of formula (VIIa) or (VIIIb) prepared as described in Method G] is subjected to a Wittig reaction with a compound of formula CH 3 OCH 2 P + Ph 3 Cl '(Ph is phenyl), for example butyllithium ( n-BuLi) to give a compound of formula (XVIII). This is then hydrolysed to give an aldehyde of formula (VIII), for example with aqueous hydrochloric acid. If desired, this aldehyde may be reduced with, for example, sodium borohydride to give the alcohol (Vc) and this may be halogenated or sulphonylated to give the compound of formula (IIIc).

Method I

In this process, a compound of formula (IX) wherein W represents a direct bond and the group -COOR3 is in the 5- or 6-position, namely a compound of formula (IXa) can be prepared as described in the following reaction scheme: 25l 31 95252 -Zn or Hg π- «VI *, 1,1,1

./Hj/Pd-C

I jTl 0 ^ j / Vx ^ COOR7-- I, XK (2) pc-ci (XVII) 1> X- | CH2L- '' '^^ COO R7 \ IXX] y'h γΐ-ICHj) p-C ^ 'S ^^^ COOR7

No (IXal 32 95252

In the above formulas, R 7, X, Y 1 and E 2 are as defined above. The dotted line means a single or double bond between the 6- and 7-positions.

5 The starting material is either a compound of formula (XV) or a compound of formula (XVII) - see Method G.

When the starting material is a compound of formula (XV), this is subjected to Clemmensen reduction using a metal such as zinc or mercury, and an acid such as hydrochloric acid or acetic acid to give a compound of formula (XIX). Alternatively, a compound of formula (XIX) may be prepared from a compound of formula (XVII) by catalytic hydrogenation using, for example, palladium on carbon or platinum oxide.

A compound of formula (XVII) or (XIX) (differing only in the presence or absence of a double bond between the 6- and 7-positions) is then subjected to a Friedel-Crafts reaction with a compound of formula X- (CH2) pC (-O) -Cl to obtain an acyl compound of formula (XX). This is then reacted with imidazole (YXH) to give the desired starting material of formula (IXa).

20

Compounds of formula (IXb): γ1- (CH2lp-C2-3a ») 030 (wherein R7, Y1, p and the dotted line are as defined above) can be prepared with the same sequence of reactions as described above, but starting with with a corresponding compound of formula (XVa) or (XVIIa):

II

33 95252 0 1 C00R7 XX ^ cxva) ^ ^ ^ CGOR7 10 I ^ (XVI Ia) (where R7 is as defined above).

15 Method J

The starting materials of formulas (Vile), (Vd) and (IIId), namely the compounds of formula (VII), (V) and (III) in which W represents a methine group in the 6-position (and thus both dashed lines denote single bonds), m 20 is 0 and Z 1 represents a methylene group which is unsubstituted or has at least one of the substituents (b), can be prepared as shown in the following reaction scheme: «34 95252, -Br-CH 2 COOR 7 - / 'N,

Π. 1 - ~ ΓΤ]> 2C00R

COOR7 V's' ^ fvCOOR7 0 (XV) (XXI) 1) HCl-HQAc fj -__ 7 Ha8H {, 2) R ^ QH / H® ^) (XXII) I JL JL coor7 l [jl 1 coor7 S Ac20 / pyridine OH OAc (ΧΧΙΙΠ fXXIY) rC ^ CHOCHi -—li JL L · COOR7 with R5CO0 3

(XXVI J

n-if ^^ l RaflHi, r-. X] 1. COOR7 I II. COOR7 ^ 0 (Vili) OH (Vd) f4 ^ ^ C ^ C0M7 1 (II Id) 35 95252

In the above formulas, R *, R5, R7 and X are as defined above. In the compound of formula (XXI), the two groups represented by R7 may be the same or different. Ac means an acetyl group.

In a first step of this process, a compound of formula (XV) is reacted with a haloacetic acid ester, preferably a bromoacetic acid ester Br-CH 2 COOR 7, to produce a compound of formula (XXI). This is then subjected to hydrolysis, decarboxylation and then esterification to give a compound of formula (XXII). Reduction of this compound of formula (XXII) by conventional means, for example sodium borohydride, gives a hydroxy compound of formula (XXIII) which is then acetylated with e.g. acetic anhydride, preferably in the presence of a base (such as pyridine) to give an acetoxy compound of formula (XXIV). Reaction of this compound with a strong base, such as p-toluenesulfonic acid, eliminates acetic acid and yields the methine compound of formula (XXV). This is then subjected to a Friedel-Crafts reaction to introduce the group R 1 -C 1 -O) to give a compound of formula (Vile). If desired, this can be reduced, e.g. with sodium borohydride, to give an alcohol of formula (Vd), which can then be halogenated or sulphonylated, if desired, to give a compound of formula (IIId).

Compounds corresponding to compounds of formulas (Vile), (Vd) and (IIId) but in which the methine group represented by W has been replaced by a methylene group may be prepared by subjecting a compound of formula (XXV) to catalytic hydrogenation, for example of a catalyst such as palladium on carbon or in the presence of platinum, oxide and then subjecting the resulting compound to the following reactions instead of the compound of formula (XXV).

In addition, the corresponding compounds having a group -W-C00R7 (where W represents a methine group or a methylene group) in the 5-position can be prepared by carrying out the same reaction sequence, but starting with a compound of formula (XVa): 0 I COOR7 35 | -p (XVa) 36 95252

(wherein R 7 is as defined above) instead of a compound of formula (XV). Method K

The starting materials of formula (III) wherein W is a direct bond, there is a double bond between the 4- and 5-positions and Z1 represents a methylene group, namely compounds of formula (IIIe)) can be prepared as described in the following reaction scheme: 10. «•» n 95252

___ COOR3 - CH, OH

I-rr ^ V ^

JI ^ J

(XXV!) (XXYII) HX __ fj-C * 2CHOCH3 + AlCl * 3 (XXVIII) j-jr ^ 5; Y ^ CH2X 1 | ^ XiClO

iL J 2) R70H

H-C s \: (XXIX)

^ V ^ CHjX

jtjTj 95252 38

In the above formulas, R 3, R 7 and X are as defined above.

In the first step of this scheme, a compound of formula (XXVI) is reduced with a suitable reducing agent such as lithium aluminum hydride to give a compound of formula 5 (XXVII). This is then halogenated or sulfonylated in conventional ways to give a compound of formula (XXVIII). The compound of formula (XVIII) is then subjected to a Friedel-Crafts reaction to introduce a formyl group at the 2-position to give a compound of formula (XXIX) which is then oxidized (e.g. with sodium chlorite) and esterified to give a compound of formula (IIIe).

Compounds corresponding to compounds of formula (IIIe) but having a double bond between the 6- and 7-positions and the group -CH 2 X in the 6-position can be prepared following the same reaction sequence described above but starting with a compound corresponding to a compound of formula (XXVI) but wherein the double bond is between the 6- and 7-positions and the group -COOR3 is in the 6-position.

Also, tetrahydrotianaphthene derivatives (e.g., compounds having simple bonds between both the 4- and 5-positions and the 6- and 7-positions) and in which the group -CH 2 X is in either the 5- or 6-position can be prepared by hydrogenation of a compound of formula (XXVI) or an analogue thereof having a double bond between the 6- and 7-positions and a group at the -COOR3 position, preferably using palladium on carbon or platinum oxide as a catalyst.

25

Method L

Compounds of formula (III) wherein W represents a direct bond, Z1 represents an optionally substituted ethylene group, the double bond is between 4-30 and 5 positions and the group -W-C00R3 is in the 5-position, namely compounds of formula (Ulf) can be prepared as follows the reaction scheme describes: 35 l / 95252 oo

Jk f * jk ^ COOR3 FXj «jCH-COO» 3. (T ^ TjSh-COOR3 (XXX) (XXXI) * 4 Q R4

Jk Jh.

hydrotysis fj jf [^ COOR3 11 KaBHi, _CO2 k.jJ \ ^ J 2) H® 1 (XXXII) R4 R4

I I

- ^ - CH ^ _ LiA- ^ Ηί, ^ CH.

1 jrr coor3. JlT ch2 ° h (XXXIII) (XXXIV) R4 "x r [i if 'l> h2x c ^ 2 CHOCH3 ks Jv ^ J + A * C * 3 (XXXV) R4> h 1 il] 11 la'e <02.

2) r 7 ° h N (XXXVI) R 4

In the above formulas, R 3, R 4, R 7 and X are as defined above. In the compound of formula (XXXI), the two groups represented by R 3 may be the same or different.

In the first step of this reaction, a longer side chain is introduced into a compound of formula (XXX) by reacting it with an optionally substituted haloacetic acid (preferably chloroacetic acid) or an ester thereof, R * CH (C1) -COOR3, to give a compound of formula (XXXI). This is then hydrolyzed and decarboxylated to give a compound of formula (XXXII) which is reduced, preferably with sodium borohydride, and dehydrated with a strong acid (e.g. p-toluenesulfonic acid) to give a compound of formula (XXXIII). This is then reduced again, this time preferably with lithium aluminum hydride to give a compound of formula (XXXIV), which is then halogenated or sulphonylated to give a compound of formula (XXXV).

This is subjected to a Friedel-Crafts reaction to give a compound of formula (XXXVI), which is then oxidized, preferably with sodium chlorite, and esterified to give the desired compound of formula (Ulf).

If desired, a compound corresponding to a compound of formula (Ulf) but wherein the double bond is between the 6- and 7-moieties and the group of formula -CH (R4) -CH2X is in the 6-position can be prepared with the same sequence of reactions but starting with a compound corresponding to a compound of formula (XXX) wherein the ketone oxygen is in the 7-position (instead of the 4-position) and the group -C00R3 is in the 6-position (instead of the 5-position).

25

If desired, the corresponding tetrahydrothianaphthene derivatives having simple bonds both between the 4- and 5-positions and between the 6- and 7-positions and having a group -CH (R 4) -CH 2 X in the 5- or 6-position can be prepared by subjecting a compound of formula (XXXIII) or an analogue thereof having a double bond between the 6- and 7-positions and a group -CH (R4) -C00R3 in the 6-position, for catalytic hydrogenation, preferably using palladium on carbon or platinum oxide as catalyst, 4.5- or 6.7-two to reduce the bis bond and then subjecting the resulting compound to the same reaction sequence as the compound of formula (XXXIII).

35 «li 41 95252

Method M

Compounds of formula (VII) wherein W represents a direct bond, the group -W-COOR 7 is in the 2-position, m is 0, the group -CH 2 is optionally substituted, the resulting group -CH (R 4) -COR 5 is in the 5-position and 4 between the - and 5-positions there is a double bond, namely compounds of formula (VIIIf), can be prepared as described in the following reaction scheme: 10 j • »·« 95252

Ri (jil

-B. INQ ^ V

(XXXIII) (XXXVII) f - rfVk «s - + A * C <3 (XXXVIII) R 'j f ^ Y NCDR5 li Ka C ^ O; [

2J H 2 OH

\ (XXXIX) ,,, _ ciXr% ° * s \ (Vlif j

II

43 95252

In the above formulas, R 3, R *, R 5, R 7 and X 'are as defined above.

In the first step of this process, a compound of formula (XXXIII) (which may be prepared as described above in connection with Method L) is converted to its corresponding acid halide, preferably an acid chloride, compound of formula (XXXVII) by reaction with a halogenating agent, e.g. thionyl chloride or phosphorus pentachloride. This is then reacted with Grignard reagent R5MgX 'to give the ketone compound 10 (XXXVIII), which is then subjected to a Friedel-Crafts reaction to give the compound of formula (XXXIX). The resulting compound is then first oxidized, e.g. with sodium chlorite, and then esterified to give the desired compound of formula (VIIIf).

A compound corresponding to a compound of formula (VIIIf) but having a double bond between the 6- and 7-positions and the -CH (R *) - COR5 group of the formula is in the 6-position can be prepared by carrying out the same sequence of reactions as described above, but starting with a compound corresponding to a compound of formula (XXXIII) but having a double bond between the 6- and 7-positions and a group 20 at the -CH 1 R 4 -COOR 36 position (this itself may be prepared as described for the corresponding compound in Method L).

Corresponding tetrahydrothianaphthene compounds having double bonds both between the 4- and 5-positions and between the 6- and 7-positions and having a group of the formula -CH (R 4) CO 5 in either the 5- or 6-position can be prepared by the same reactions as above. described except that the starting material of formula (XXXIII) or an analogue thereof having a double bond between the 6- and 7-positions and a group of the formula -CH (R 1) -C00R 3 at the 6-position is hydrogenated (preferably in the presence of palladium on carbon or platinum oxide as catalyst) and the resulting hydrogenated compound is then subjected to the above reaction sequence.

Method N

Compounds of formula (IX) wherein W represents a direct bond, E is 0, the double bond is between the 4- and 5-positions and the group -C00R3 is in the 2-position, namely compounds of formula (IXb) can be prepared as described in the following reaction scheme: 95252

^ s ^ CQ0H T

gcr ^ -gcr [XXVia) (XL) 0 CH3Mg8r _ π-C ^ CH2OCH3_ $ J (XII)

0 I

I-11 11 f] -rV: H3

ASV 2ir? Oh 7 ASAA

HC. 5 S700C 3 0 IXUII 1XLIII] 0 Ö

[Br] [Π Τ ^ γ ^: Η28Γ yV

(XLIV] "0 πΓΤ ^ 1 (IXb) 45 95252

In the above formulas, R7 and Y1 are as defined above.

In the first step of this reaction, the compound of formula (XXVIa) is converted to its acid halide, e.g. acid chloride (XL), by reaction with a halogenating agent, for example thionyl chloride, phorp pentachloride or phosphorus oxychloride. The resulting acid halide (XL) is then in turn subjected to the following reactions: reaction with a Grignard reagent of formula CH 3 MgBr to give the ketone compound (XLI);

Friedel-Crafts reaction to obtain aldehyde (XLII); oxidation, preferably with sodium chlorite and then esterification to give the ester (XLIII); bromination to give bromide (XLIV); and finally reaction with imidazole (YXH) to give a compound of formula (IXb).

The corresponding compound having a double bond between the 6- and 7-positions and the group-C (= O) -OΗΗΥχ at the 6-position can be prepared by the same reaction sequence, but starting with a compound corresponding to the compound of formula (XXVIa) but wherein there is a double bond between the 6- and 7-positions and the group -C00H is in the 6-position.

Corresponding tetrahydrothianaphthene compounds having simple bonds both between the 4- and 5-positions and between the 6- and 7-positions and having the group -C (= O) -GH2Y1 in either the 5-position or the 6-position can be prepared by hydrogenation of the formula ( XXVIa) a compound or an analogue thereof having a double bond between the 6- and 7-positions and a carboxyl group at the 6-position, preferably using palladium on carbon or platinum oxide as a catalyst.

Method 0 Compounds of formula (III) wherein W represents a vinylene group, the group -W-C00R3 is in the 2-position, there is a double bond between the 4- and 5-positions, Z1 represents a methylene group and the group -CH2X (e.g.-Zx-X) is At the 5-position, namely compounds of formula (IIIg), can be prepared by the Wittig reaction from a compound of formula (XXIX) (see Method K) as described in the following reaction: • · <46 95252

_ CH? X

- r7oqc (II Ig) 10

The corresponding compound having a double bond between the 6- and 7-positions and having a group -CH 2 X at the 6-position can be prepared by the same reaction but starting with an analog of a compound of formula (XXIX) wherein the double bond and the group -CH 2 are at those positions.

Similarly, tetrahydrothianaphthene derivatives having double bonds both between the 4- and 5-positions and between the 6- and 7-membered moieties and having the group -CH 2 X in either the 5-position or the 6-position can be prepared by first hydrogenating a compound of formula (XXIX) or the aforementioned analog thereof before performing the Wittig reaction.

Method P

Compounds of formula (III) wherein W represents a methylene group, the group -W-C00R3 represents a methylene group, the group -W-C00R3 is in the 2-position, a double bond is present between the 4- and 5-positions, Z1 represents a methylene group and the group -CH2X (e.g. -ZJ-X) in the 5-position, namely compounds of formula (IIIh), can be prepared as described in the following reaction scheme:

II

47 95252 I i | Τ + PhjPnrHjOCHjCi0 HC 's (XXIX) fU y ___ ^ /% r / CH2x + Ä) Γ at rfl, u

- ®S

MeO 5 - * “(XU) _ci ^ x

MtOOC ^ J ^ L ^.

llllhl • »t 48 95252

In the above formulas, X and Ph are as defined above.

In the first step of this reaction, a compound of formula (XXIX) is subjected to a Wittig reaction to form a double bond at the 2-position side chain 5 and to give a compound of formula (XLV). This is then oxidized, suitably with pyridinium chlorochromate, to give the desired compound of formula (IIIh).

Compounds corresponding to compounds of formula (IIIh) but having a double bond between the 6- and 7-positions and in which the group -CH 2 X is a 6-position-10 mass can be prepared with the same reaction sequence but starting with an analog of the compound of formula (XXIX) wherein the double bond is present between the 6- and 7-positions and the group -CH2X is present at the 6-position.

Corresponding tetrahydrothianaphthene derivatives having simple bonds both between the 4- and 5-positions and between the 6- and 7-positions and having the group -CH 2 X in either the 5-position or the 6-position can be prepared by first halogenating the compound of formula (XXIX) or its the above analog before performing the Wittig reaction and then oxidation.

In all of the above processes, the G-P starting materials in which R1 and / or R2 represent an alkyl group can be prepared by exactly the hinged methods, but using the corresponding starting materials having one or more alkyl substituents in a suitable position.

When the starting materials are prepared as esters, they may, if desired, be converted to the free acid by conventional hydrolysis reactions before use.

The compounds of the present invention may contain one or more asymmetric carbon atoms and thus may exist in the form of various optical isomers. If necessary, individual optical isomers can be prepared using specific isomers of the starting materials and / or stereospecific synthetic techniques. Alternatively, if a mixture of isomers is prepared from any of the above reactions, the individual isomers can be obtained by conventional optical resolution techniques. Alternatively, a mixture of isomers may be used. Although all isomers are represented above by a single structural formula, the present invention encompasses both the individual isolated isomers and mixtures thereof.

The compounds of the present invention have been found to have excellent ability to inhibit platelet aggregation and inhibit TXA2 synthetase activity, resulting in excellent anti-thrombotic activity, as demonstrated in the pharmacological tests mentioned below.

Thus, the compounds of the invention have shown 100% inhibition of collagen-induced flake aggregation in rabbit flake-rich plasma at concentrations of the order of 10'5 g / ml and 50% inhibition of TXA2 biosynthesis at molar concentrations of the order of 10'8. On the other hand, the inhibitory activities against cyclooxygenase and prostacyclin synthetase are very weak, indicating that the compounds of the present invention are relatively inactive against other metabolically important enzymes, which is an advantage. In in vivo test systems, the compounds of the present invention have been shown to have a significant inhibitory effect on oral mortality due to thrombotic disorders caused by intravenous arachidonic acid in mice and rabbits. These experiments are considered to serve as good experimental models for demonstrating the expected activity in humans.

In particular, the lack of activity against cyclooxygenase and protacycline synthetase indicates that the compounds of the invention do not inhibit the synthesis of other prostaglandin derivatives.

Accordingly, the compounds of the present invention are expected to be of value in the therapy and treatment of diseases and disorders caused by imbalances in blood TXA2 levels, e.g., inflammation, overexertion, thrombosis, cerebral hemorrhage, and asthma, and are expected to be particularly useful in treating thrombosis in mammals. including man. For example, they are expected to be useful in the treatment and management of myocardial infarction, cerebral thrombosis, and bloodless peripheral vascular diseases, as well as in the treatment of postoperative thrombosis and to accelerate the expansion of transplanted vessels after surgery.

The compounds of the invention may be ingested by any suitable route, orally or parenterally, and may be formulated accordingly, for example: for oral ingestion as tablets, capsules, powders, granules or syrups or parenterally as suppositories or injectable subcutaneous solutions or suspensions.

10

The compounds of the invention may be formulated with conventional pharmaceutical carriers or diluents or may be ingested as such.

The dosage amount of a compound of the invention will vary depending on the nature and severity of the disease or disorder being treated, age, body weight, symptoms, and the condition and mode of administration of the patient. However, as a guide, the adult human dose can be expected to be 50-1800 mg per day, which is preferably ingested in divided doses, e.g., about 2- or 20 3 times a day.

The preparation of certain compounds of the invention is further described in the following Examples 1-45, while the preparation of certain starting materials used in these examples is described in the following Preparations. The biological activity of the compounds of the invention is described in Experiments 1 and 2. In the nuclear magnetic resonance spectra, tetramethylsilane was used as an internal standard in all examples.

Example 1 . 30

Methyl 4,5-dihydro-2- (1-imidazolyl) methylmethanephthene-6-carboxylate 1 (a) 0.14 g of sodium borohydride was added to a solution of 0.75 g of methyl 2-formyl-4,5-dihydrothianaphthene-6-carboxylate. in a mixture of methanol and tetrahydrofuran (4 ml each) at 3 [deg.] C. and the mixture was stirred for 30 minutes, after which time the reaction mixture was concentrated by evaporation under reduced pressure. to dryness under reduced pressure to give 0.75 g of methyl 4,5-dihydro-2-hydroxymethylthianaf-5-thene-6-carboxylate.

1 (b) A solution of 0.73 ml of thionyl chloride in 10 ml of methylene chloride was added dropwise to a solution of 2.98 g of imidazole and 20 mg of 4-dimethylaminopyridine in 60 ml of methylene chloride, and the mixture was stirred for 30 minutes. A solution of 0.75 g of methyl 4,5-dihydro-2-hydroxymethylthianaphthene-6-carboxylate [prepared as in step (a) above] in 10 ml of methylene chloride was added dropwise to the solution, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then concentrated by evaporation under reduced pressure. Residue 15 was extracted with a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. The extract was washed 5-6 times with water, dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting syrupy substance was purified by column chromatography through silica gel, eluting with a 50: 1: 1 by volume mixture of ethyl acetate, ethanol and triethylamine to give 0.21 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.80 (3H, singlet); 5.22 (2H, singlet).

Example 2

Sodium 4,5-dihydro-2- (1-imidazolyl) methylthianaphthene-β-carboxylate and its hydrate 0.21 g of methyl 4,5-dihydro-2- (1-imidazolyl) methylthianaphthene-6-carboxylate (prepared as in Example 1) 1 is described) was hydrolyzed in aqueous ethanolic sodium hydroxide solution, ethanol 35 was distilled off under reduced pressure, the resulting aqueous solution was washed with diethyl ether and then evaporated to dryness.

Infrared Absorption Spectrum (Nujol trade name-Mull) μm cm -1: δ 1650, 1550.

Elemental analysis:

Calculated for C 13 H 11 N 2 O 2 SNa.H 2 O: C, 51.99%; H, 3.79%; N, 9.33%; S, 10.68%.

Found: C, 52.11%; H, 3.78%; N, 9.43%; S, 10.25%.

The amorphous solid obtained as described above was recrystallized from 80% v / v aqueous methanol-acetone to give the corresponding anhydride as pale yellow needles (m.p.> 300 ° C).

15

Elemental analysis i:

Calcd for C 18 H 11 N 2 O 2 SNa: C, 55.31%; H, 3.93%; N, 9.92%; S, 11.36%.

Found: C, 55.53%; H, 3.96%; N, 10.08%; S, 11.24%.

20

Example 3

Methyl 4,5-dihydro-2-α- (1-imidazole-benzyl) thianaphthene-6-carboxylate 0.40 g of methyl 2-benzoyl-4,5-dihydrothianaphthene-6-carboxylate was reduced with sodium borohydride in the same manner as in Example 1 (a). The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was extracted with a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. The resulting crude oil was subjected to column chromatography through silica gel using ethyl acetate as the eluent to give 0.21 g of the title compound.

• <53 95252

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.79 (3H, singlet); 6.65 (2H, singlet).

5 Example 4

Sodium 4,5-dihydro-2 - [(1-iroidazolyl) benzyl] thianaphthene-6-carboxylate trihydrate 0.21 g of methyl 4,5-dihydro-2- [α- (1-imidazolyl) benzyl] thianaphthene-6-carboxylate ( prepared as described in Example 3) was hydrolyzed with aqueous ethanolic sodium hydroxide solution. The ethanol was then distilled off under reduced pressure. The resulting aqueous solution was washed with diethyl ether and then evaporated to dryness. The resulting powder was reprecipitated from ethanol-diethyl ether to give 70 mg of the title compound as a colorless amorphous powder.

Infrared Absorption Spectrum (Nujol Mull) ν max: 1690, 1460.

20

Elemental analysis:

Calculated for C ^ H ^ N ^ SNa. 3H 2 O: C, 55.33%; H, 5.13%; N, 6.79%; S, 7.77%.

Found: C, 55.23%; H, 4.85%; N, 7.05%; S, 7.79%.

: 25

Example 5

Methyl? [2- (1-imidazolyl) ethyl] -4-dihydrothianaphthene-6-carboxylate 5 (a) Methyl 2 - 2- (1-imidazolyl) -1-oxoethyl-4,5-dihydrothianaphthene-6-carboxylate

The Friedel-Crafts reaction was performed using 15.0 g of methyl 4,5-dihydro-35-rotianaphthene-6-carboxylate, 20.6 g of aluminum chloride and 8.3 ml of bromoacetyl chloride. The reaction mixture was then poured into ice water and stirred for 1 hour. The mixture was then extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and then evaporated to dryness under reduced pressure to give a crude crystalline substance containing methyl 2- (2-bromo-1-oxoethyl) -4,5-dihydrothianaphthene-6-carboxylate. . The crude crystalline substance thus obtained was dissolved in a mixture of 300 ml of methanol and 150 ml of tetrahydrofuran. To the resulting solution was added 18.4 g of imidazole, and the mixture was heated under reflux for 2 hours. After this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was washed alternately with saturated aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The solution was then filtered and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 40: 1: 1 by volume mixture of ethyl acetate, ethanol and triethylamine as the eluent to give 20.16 g of the title compound 15 as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3 δ ppm: 3.85 (3H, singlet); 5.20 (2H, singlet).

20 5 (b) Methyl 2- {2- (1-imidazolyl) -1-methylthio (thiocarbonyl) oxyethyl] -4,5-dihydrothianaphthene-6-carboxylate 2.01 g of methyl 2- [2- (1-imidazolyl) ) -1-oxoethyl] -4,5-dihydrothianaphthene-6-carboxylate [prepared as described in step (a) above] was reduced with sodium borohydride in the same manner as in Example 1 (a) to give 1.72 g of alcohol. This was dissolved in tetrahydrofuran, 0.30 g of sodium hydride was added to the resulting solution at 3 ° C, and the mixture was stirred at 50 ° C for 1 hour. The mixture was then cooled by standing at room temperature. 1.7 ml of carbon disulfide and 1.76 ml of methyl iodide were added in this order, and the mixture was stirred at room temperature for 20 minutes. After this time, the reaction mixture was poured into a mixture of ice water and 0.39 ml of glacial acetic acid and extracted with ethyl acetate. The extract was washed alternately with saturated aqueous sodium bicarbonate and aqueous sodium chloride. The solution was then dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 8: 1: 1 by volume mixture of ethyl acetate, ethanol and triethylamine as an eluent to give 1.03 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 2.40 (3H, singlet); 3.79 (3H, singlet).

5 (c) Methyl 2- [2- (1-imidazolyl) ethyl] -4,5-dihydrothianaphthene-6-10 carboxylate 1.00 g methyl 2- [2- (1-imidazolyl) -1-methylthio (thiocarbonyl) oxy -ethyl] -4,5-dihydrothianaphthene [prepared as described in step (b) above] was dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of toluene. To the solution was added 1.0 ml of tributyltin hydride in the presence of a catalytic amount of azobisisobutyronitrile, and the mixture was heated under reflux for 1 day under a nitrogen atmosphere. After this time, the reaction mixture was concentrated by distilling off the solvent under reduced pressure, and a solution of the residue in acetonitrile was washed with hexane. Acetonitrile-20 was then removed by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography using a 30: 1: 1 by volume mixture of ethyl acetate, ethanol and triethylamine as an eluent to give 0.51 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.16 (2H, triplet); 3.80 (2H, singlet); 4.19 (2H, triplet); 7.42 (1H, singlet).

30

Example 6

Sodium 2 - ((1-imidazolyl) ethyl 4,5-dihydrothianaphthene-6-carboxylate 0.45 g of methyl 2- [2- (1-imidazolyl) ethyl] -4,5-dihydrothianaphthene-6-carboxylate (prepared as described in Example 5) was hydrolyzed with sodium hydroxide in the same manner as in Example 2 to give a solid which was reprecipitated from methanol and diethyl ether to give 0.37 g of the title compound as a colorless, amorphous powder.

5

Infrared Absorption Spectrum (Nujol Mull) tw ^ cnf1: 1630, 1560.

Elemental analysis: Calculated for C 14 H 13 N 2 O 2 SNa: C, 56.75%; H, 4.42%; N = 9.45%; S, 10.82%.

Found: C, 56.58%; H, 4.70%; N, 9.44%; S, 10.59%.

Example 7 15

Methyl 4,5,6,7-tetrahydro-2- (1-imidazolyl) methyl] naphthene-6-carboxylate Using the same procedure as described in Example 1, 0.20 g of the title compound was obtained as an oily substance from 0.34 g of 2-formyl-4-carboxylate. , 5,6,7-tetrahydrotyanaphthene-6-carboxylate.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.77 (3H, singlet); Δ 5.20 (2H, singlet).

Example 8

Sodium 4.5.6.7-tetrahydro-2- (1-imidazolyl) methylthianaphthene-6-carboxylate 0.30 g methyl 4,5,6,7-tetrahydro-2- (1-imidazolyl) methylthianaphthene-6-carboxylate (prepared as described in Example 7) was hydrolyzed with sodium hydroxide in the same manner as described in Example 2 to give a solid which was recrystallized from ethanol-diethyl. from the ether to give 0.19 g of the title compound as a colorless, amorphous powder.

li 57 95252

Infrared Absorption Spectrum (Nujol Mull) Uu ^ cnf1: 1560.

Elemental analysis: Calculated for C 13 H 13 N 2 O 2 SNa: C, 54.92%; H, 46.09%; N, 9.85%; S, 11.28%.

Found: C, 54.68%; H, 45.87%; N, 9.91%; S, 11.45%.

Example 9 10

Methyl 2- [2- (1-imidazolyl) ethyl] -4,5,6,7-tetrahydrothianaphthene-6-carboxylate 9 (a) Methyl 2- [2- (1-imidazolyl) -1-oxoethyl] -4,5,6,7-tetrahydro- Thianaphthene-6-carboxylate Using the same procedure as described in Example 5 (a), 0.54 g of the title compound was obtained as an oily substance from 0.80 g of methyl 4,5,6,7-tetrahydrothianaphthene-6-carboxylate.

20

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.74 (3H, singlet); 5.22 (2H, singlet).

25 9 (b) Methyl 2- {2- (1-imidazolyl) -1-methylthio (thiocarbonylloxyethyl) 4,5,6,7-tetrahydrothianaphthene-6-carboxylate Using the same procedure as described in Example 5 (b), 0.42 g was obtained. the title compound as an oily substance from 0.54 g of ketones prepared as described in step 30 (a) above.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 2.38 (3H, singlet); 3.77 (3H, singlet).

»* 35 95252 58 9 (c) Methyl 2- [2- (1-imidazolyl) ethyl-4,5,6,7-tetrahydrothianaphthene-6-carboxylate 0.41 g of xanthate ester [prepared as described in step (b) above] was subjected to free radical reduction with tributyltin hydride in the same manner as described in Example 5 (c) to give 0.28 g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.18 (2H, triplet); 3.79 (3H, singlet); 4.20 (2H, triplet).

Example 10 2 - Γ 2- (1-Imidazolvolvetyl) -4.5.6.7-tetrahydrothianaphthene-6-carboxylic acid hydrochloride

A solution of 0.25 g of methyl 2- [2- (1-imidazolyl) ethyl] -4,5,6,7-20 tetrahydrothianaphthene-6-carboxylate (prepared as described in Example 9) in a mixture of 5 ml concentrated hydrochloric acid and 5 ml of glacial acetic acid, was heated at reflux for 4 hours. After this time, the reaction mixture was evaporated to dryness by distilling off the solvent under reduced pressure, and the resulting solid residue was recrystallized from a mixture of ethanol and diethyl ether to give 0.19 g of the title compound as a colorless amorphous powder.

Infrared Absorption Spectrum (Nujol Mull) ν cm -1: 1720.

30 * * ·

Elemental analysis:

Calculated for C1AH16N202S. HCl: C, 53.76%; H, 5.48%; N, 8.96%; S, 10.25%; Cl, 11.33% Found: C, 53.72%; H, 5.73%; N, 9.01%; S, 9.95%; Cl, 11.30%. 1 35 • i

II

59

Example 11 95252 4.5.6.7-Tetrahydro-2- (1-imidazolyl) methyl-6-methoxycarbonylmethylidene thianaphthene Using the same procedure as described in Example 1, 0.39 g of the title compound was obtained as an oily substance from 1.50 g of 2-formyl- 4.5.6.7-Tetrahydro-6-methoxycarbonylmethylidene thianaphthene.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.68 (3H, singlet); 5.20 (2H, singlet); 6.25 (1H, singlet); 6.73 (1H, singlet).

15

Example 12 4.5.6.7-Tetrahydro-2- (1-imidazolyl) methyl-6-carboxymethylidene-thianaphthene sodium salt 0.29 g of 4,5,6,7-tetrahydro-2- (1-imidazolyl) methyl-6-methoxycarbonyl -Methylidenethanaphthene (prepared as described in Example 11) was hydrolyzed with sodium hydroxide in the same manner as described in Example 2 to give a solid which was reprecipitated from ethanol-diethyl 25-ether to give 0.20 g of the title compound as a pale yellow amorphous powder.

Infrared absorption spectrum (Nujol Mull) ν max cm -1: 1580.

30 Elemental analysis:

Calcd for C 11 H 13 N 2 O 2 SNa C, 56.75%; H, 4.42%; N, 9.45%; S, 10.82%.

Found: C, 57.03%; H, 4.18%; N, 9.40%; S, 11.08%.

»· E 35 60

Example 13 95252

Methyl 4,6,7-tetrahydro-2-yl (3-pyridyl) methyl 1-cyanaphthene-6-carboxylate 5 13 (a) Methyl 4,5-dihydro-2 - [(hydroxy) (3-pyridyl) methyl] thianaphthene 6-Carboxylate 12 ml of a 15% w / w solution of butyllithium in hexane was added to a solution of 2.17 ml of 3-bromopyridine in 40 ml of diethyl ether at -78 ° C under a nitrogen atmosphere and the mixture was stirred for 30 minutes. A solution of 2.5 g of methyl 2-formyl-4,5-dihydrothianaphthene-6-carboxylate in a mixture of diethyl ether and tetrahydrofuran of 20 ml each was then added dropwise. The mixture was then warmed to room temperature over one hour and then poured into aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as an eluent to give 1.61 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.80 (3H, singlet); 5.94 (1H, singlet); Δ 6.65 (1H, singlet).

13 (b) Methyl 4,5,6,7-tetrahydro-2 - [(3-pyridyl) methyl] thianaphthene-6-carboxylate 1.0 g of methyl 4,5-dihydro-2 - [(hydroxy) (3-pyridyl) methyl] thianaphthene The 6-carboxylate [prepared as described in step (a) above] in ethanol was reduced in the presence of 1N aqueous hydrochloric acid (3.48 ml) over a 10% by weight palladium on carbon catalyst (2.0 g) and a hydrogen atmosphere. When the reduction was completed, the reaction mixture was adjusted to pH 8 by adding aqueous sodium bicarbonate solution. The mixture was then filtered and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was dissolved in ethyl acetate and the solution was washed with aqueous sodium chloride solution. The solution was then dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography using a 1: 2 by volume mixture of hexane and ethyl acetate as the eluent to give 0.15 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.71 (3H, singlet); 4.08 (2H, singlet): 6.44 (1H, singlet).

Example 14 4.5.6.7-Tetrahydro-2 - [(1-pyridylmethyl] thianaphthene-6-carboxylate hydrochloride 0.15 g Methyl 4,5,6,7-tetrahydro-2 - ((3-pyridyl) methyl] thianaphthene-6-carboxylate (prepared as described in Example 13) was dissolved in a mixture of concentrated hydrochloric acid and glacial acetic acid (2 ml each), and the mixture was heated under reflux for 9 hours, after which time the reaction mixture was evaporated to dryness under reduced pressure and the resulting residue was recrystallized. from diethyl ether to give 0.12 g of the title compound as colorless needles, melting at + 205-208 ° C.

Elemental analysis:

Calculated for C15H15NO2S. HCl: C, 58.15%; H, 5.21%; N, 4.52%; S, 10.35%; Cl, 11.48%.

Found: C, 57.89%; H, 5.45%; N, 4.50%; S, 10.41%; Cl, 11.55%.

• · ___ ··· 1— 95252 62

Example 15

Methyl 2- [2- (1-imidazolyl) vinyl] -4,5-dihydrothianaphthene-6-carboxylate 5 1.02 g of methyl 2- [2- (1-imidazolyl) -1-oxoethyl] -4,5-dihydrothianaphthene The 6-carboxylate [prepared as described in Example 5 (a)] was reduced with sodium borohydride in the same manner as described in Example 1 to give 0.87 g of the corresponding alcohol. A solution of this alcohol in 100 ml of toluene was heated at reflux for 2 hours in the presence of p-toluenesulfonic acid monohydrate (0.59 g). After this time, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 40: 1: 1 by volume mixture of ethyl acetate, ethanol and triethylamine as an eluent to give 0.58 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.79 (3H, singlet); 6.5-7.3 (6H, multiplet); 7.75 (1H, singlet).

25 Example 16

Sodium 2- {2- (1-imidazolyl) vinylene 1-4,5-dihydrothianaphthene-6-carboxylate 0.38 g of methyl 2- [2- (1-imidazolyl) vinylene] -4,5-dihydrothianaphthene- "6- the carboxylate (prepared as described in Example 15) was hydrolyzed with sodium hydroxide in the same manner as in Example 2, and the solid product was recrystallized from a mixture of ethanol and diethyl ether to give 0.29 g of the title compound as a colorless, amorphous powder.

63 95252

Infrared Absorption Spectrum (Nujol Mull) ν cm -1: 1635, 1560.

Elemental analysis: Calculated for C 11 H 11 N 2 O 2 SNa C, 57.14%; H, 3.77%; N, 9.52%; S, 10.89%.

Found: C, 56.89%; H, 3.88%; N, 9.56%; S, 11.21%.

Example 17 10 6 - .54.5.6.7- (Tetrahydro-2- (1-imidazolyl) methylthianaphthene] carboxylic acid hydrochloride

A solution of 2.90 g of methyl 4,5,6,7-tetrahydro-2- (1-imidazolyl) -15 methylthianaphthene-6-carboxylate (prepared as described in Example 7) in 30 ml of concentrated hydrochloric acid and 30 ml of glacial acetic acid, was heated at reflux for 3 hours. After this time, the reaction mixture was evaporated to dryness under reduced pressure and the residue was treated to give a crude crystalline material which was then recrystallized from 95% v / v water-20 ethanol-acetone to give 22.55 g of the title compound as colorless needles melting at 197-198 ° C.

Infrared Absorption Spectrum (KBr) λmax cm -1: 1720.

25

Elemental analysis:

Calculated for C13HuN2O2S. HCl: C, 52.26%; H, 5.06%; N, 9.38%; S, 10.73%; Cl, 11.87%. Found: C, 52.15%; H, 5.09%; N, 9.31%; S, 10.63%; Cl, 11.77%.

30 * Example 18

Methyl 6.7-dihydro-2 - [(1-imidazolyl) methyl] thianaphthene -5-carboxylate 35

A solution of 0.78 ml of thionyl chloride in 4 ml of methylene chloride was added to a solution of 2.91 g of imidazole in methylene chloride, 64 95252, and the mixture was stirred for 30 minutes. A solution of 0.96 g of methyl 6,7-dihydro-2- (hydroxymethyl) thianaphthene-5-carboxylate in 15 ml of methylene chloride was then added dropwise. The reaction mixture was stirred for 15 hours at room temperature, after which the solvent 5 was removed by distillation under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solution was washed alternately with aqueous sodium bicarbonate solution and aqueous sodium chloride solution. It was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using a 20: 1: 1 mixture of ethyl acetate, ethanol and diethylamine as an eluent to give 0.76 g of the title compound. This product was recrystallized from acetone-hexane to give pale yellow needles melting at 87.0-89.0 ° C.

15 Example 19

Natriuric- (6,7-dihydro-2 - [(1-imidazolyl) methyl] thianaphthene) carboxylate hemihydrate 0.13 g methyl 6,7-dihydro-2 - [(1-imidazolylmethyl)] thianaphthene-5-carboxylate (prepared as described in Example 18) was hydrolyzed with sodium hydroxide in ethanol in a conventional manner. The ethanol was distilled off under reduced pressure and the residual aqueous phase was washed with diethyl ether and then evaporated to dryness under reduced pressure. The resulting product was recrystallized from methanol-acetone to give 0.10 g of the title compound as pale green needles which did not melt at 260 ° C.

Elemental analysis:

Calculated for C13H11N2O2SNa. For 1/2 H 2 O: 30 C, 53.60%; H, 4.15%; N, 9.62%; S, 11.01%.

** Found: C, 53.77%; H, 3.97%; N, 9.19%; S, 11.10%.

• · 65

Example 20 95252

Methyl 4,5,6,7-tetrahydro-2 - [(1-imidazolyl) methyl] thianaphthene-5-carboxylate 0.30 g of methyl 6,7-dihydro-2 - [(1-imidazolyl) methyl] thianaphthene-5-carboxylate ( prepared as described in Example 18) was catalytically hydrogenated in the presence of 10% by weight of palladium on carbon (1.0 g) and 1N aqueous hydrochloric acid (1.15 ml) under a hydrogen atmosphere. After this time, the reaction mixture was adjusted to pH 8 by adding aqueous sodium bicarbonate solution and then filtered. The filtrate was concentrated by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. It was then filtered and concentrated by evaporation under reduced pressure to give 0.12 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.70 (3H, singlet); Δ 5.14 (2H, singlet); 6.65 (1H, singlet).

Example 21-25 5-14,5,6,7-Tetrahydro-2 - [(1-imidazolyl) methyl] itaphenene) carboxylic acid hydrochloride 1/4 hydrate

A solution of 0.12 g of methyl 4,5,6,7-tetrahydro-2 - [(1-imidazolyl) methyl] thianaphthene-5-carboxylate (prepared as described in Example 30) in 3 ml of concentrated hydrochloric acid and in 3 ml of glacial acetic acid, * was heated at reflux for 4 hours. After this time, the reaction mixture was evaporated to dryness by distilling off the solvent under reduced pressure. The residue was recrystallized from a mixture of ethanol and diethyl ether to give 0.09 g of the title compound as colorless flake-like crystals, melting at 353.0-215.0 ° C.

66 95252

Elemental analysis:

Calculated. HCl.1 / 4 for H 2 O: C, 51.48%; H, 5.15%; N, 9.23%; S, 10.57%; Cl, 11.69%. Found: C, 51.17%; H, 5.16%; N, 9.09%; S, 10.40%; Cl, 11.82%.

5

Example 22

Me twl i>. 7-dihydro-2-βα (1-imidazolyl) benzyl 11 ianaphthene - 5-carboxylate 10

A solution of 1.22 ml of thionyl chloride in 10 ml of methylene chloride was added to a solution of 4.92 g of imidazole in 20 ml of methylene chloride, and after 30 minutes a solution of 1.67 g of methyl 2 - [(hydroxy) was added dropwise. ) (phenyl) methyl] thianaphthene-5-15 carboxylate in 30 ml of methylene chloride under a nitrogen atmosphere. After 10 minutes, the reaction mixture was concentrated and treated in the same manner as described in Example 18. The resulting residue was subjected to silica gel column chromatography using ethyl acetate as an eluent to give 1.26 g of the title compound as a pale brown oily substance.

20

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.77 (3H, singlet); 6.64 & 6.70 (each 1H, both singlets).

25 Example 23

Sodium 5- (6,7-dihydro-2-failimidazolyl) benzyl 1 thianaphthene) carboxylate dihydrate 30 Using the same procedure as described in Example 19, 0.15 g of methyl ** 6,7-dihydro-2 - [(1 -imidazolyl) benzyl] thianaphthene-5-carboxylate (prepared as described in Example 22) was hydrolyzed with sodium hydroxide and the product was remixed from a mixture of ethanol and diethyl ether to give 0.09 g of the title compound as a colorless amorphous powder.

• i t

II

95252 67

Infrared Absorption Spectrum (Nujol Mull) λmax cm @ -1: 1550.

Elemental analysis: Calculated for C 19 H 15 N 2 O 2 SNa.2H 2 O: C, 57.86%; H, 4.86%; N, 7.10%; S, 8.13%.

Found: C, 57.49%; H, 4.11%; N, 6.89%; S, 8.01%.

Example 24 10

Methyl & 5,6,7-tetrahydro-2 - [(3-pyridyl) methyl] thianaphthene-5-carboxylate 24 (a) Methyl 6,7-dihydro-2 - [(hydroxy) (3-pyridyl) methyl] thianaphthene-5- carboxylate 12 ml of a 15% w / w solution of butyllithium in hexane was added to a solution of 2.17 ml of 3-bromopyridine in 40 ml of diethyl ether at -78 ° C under a nitrogen atmosphere and the mixture was stirred for 30 minutes.

A solution of 2.5 g of methyl 2-formyl-6,7-dihydrothianaphthene-5-carboxylate in a mixture of diethyl ether and tetrahydrofuran of 20 ml each was added dropwise. The reaction mixture was then warmed to room temperature over about one hour and poured into aqueous ammonium chloride solution. It was then extracted with ethyl acetate.

The extract was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as an eluent to give 1.61 g of the title compound as a pale brown oily substance.

30

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.74 (3H, singlet); 5.95 (1H, singlet); 6.67 (1H, singlet).

• · «35 68 95252 24 (b) Methyl 4.5,6,7-tetrahydro-2-yl (3-pyridyl) methylthianaphthene-5-carboxylate 1.0 g of methyl 6,7-dihydro-2 - [(hydroxy) (3- pyridyl) methyl] thianaphthene-5-carboxylate [prepared as described in step (a) above] was catalytically reduced in the presence of 10% by weight of palladium on carbon (2 g) and 1N hydrochloric acid solution (3.48 ml) under a hydrogen atmosphere. The reaction mixture was then treated as described in Example 20. The product was subjected to silica gel column chromatography using a 1: 2 by volume mixture of hexane and ethyl acetate as the eluent to give 0.12 g of the title compound as a pale yellow oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.71 (3H, singlet); 4.03 (2H, singlet); 6.47 (1H, singlet).

Example 25 5 - (2 - [(3-pyridyl) methyl] -4,5,6,7-tetrahydrothianaphthene) carboxylic acid hydrochloride 1/4 hydrate

A solution of 0.12 g of methyl 4,5,6,7-tetrahydro-2 - [(3-pyridyl) methyl] thianaphthene-5-carboxylate [prepared as described in Example 25 24 (a)] as a mixture of concentrated hydrochloric acid and glacial acetic acid (2 mL each) was heated at reflux for 10 hours. After this time, the reaction mixture was evaporated to dryness. The resulting residue was recrystallized from a mixture of ethanol and diethyl ether to give 0.10 g of the title compound as colorless needles, melting at 227-229 ° C.

30

Elemental analysis:

Calculated for C 15 H 15 NO 2 .HCl.1 / 4 H 2 O: C, 57.32%; H, 5.29%; N, 4.46%; S, 10.20%; Cl, 11.28%. Found: C, 57.70%; H, 5.38%; N, 4.23%; S, 10.03%; Cl, 11.50%.

• · n 35 69

Example 26 95252

Me twig - i2 - (‘1-imidazolyl] -6,7-dihydrothianaphthene-5-carboxylate 5

A solution of 200 mg of imidazolyl in 4 ml of dimethylformamide was added dropwise to a suspension of 70 mg of sodium hydride (55% by weight as a suspension in mineral oil) in 2 ml of dimethylformamide at room temperature under a nitrogen atmosphere. After 15 minutes, a solution of 0.19 g of methyl 2- (2-methanesulfonyloxyethyl) -6,7-dihydrothianaphthene-5-carboxylate in 4 ml of dimethylformamide was added dropwise thereto, and the mixture was stirred at room temperature for one hour. After this time, the reaction mixture was poured into ice water and stirred for 1 hour. It was then extracted with ethyl acetate. The extract was washed well with water, dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 10: 1: 1 by volume mixture of ethyl acetate, ethanol and triethylamine as an eluent to give 90 mg of the title compound as a pale brown oily substance.

20

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.80 (3H, singlet); 6.56 (1H, singlet).

: 25 Example 27

Sodium 5-2- [2- (1-imidazolyl] ethyl-6,7-dihydrothianaphthenecarboxylate Using the same procedure as described in Example 19, 30 mg of methyl 2- [2- (1-imidazolyl) ethyl] -6,7-dihydrothianaphthene -5-Carboxylate (prepared as described in Example 26) was hydrolyzed with sodium hydroxide and the product recrystallized from a mixture of ethanol and diethyl ether to give 20 mg of the title compound as colorless needles melting at 180-183 ° C (decomposed).

<· 70

Example 28 95252 4.5.6.7 -Tetrahydro-2 - [(1-imidazolyl) methyl] -5-methoxycarbonylmethylidene thianaphthene 5 Using the procedure obtained as described in Example 18, 0.29 g of the title compound was obtained as a pale brown oily substance, 1.24 g. from 4.5.6.7 - te trhydro-2-hydroxy absorbed from 1 to 5-methoxycarbonyl absorbed from 1 idea naphthenic.

10

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.71 (3H, singlet); 5.16 (2H, singlet); 6.24 (1H, singlet); Δ 6.70 (1H, singlet).

Example 29 f 2- (1-Imidazolylmethyl 1-5-carboxymethylidene thianaphthene sodium 20 salt Using the same procedure as described in Example 19, 0.29 g of 4.5.6.7-tetrahydro-2 - [(1-imidazolyl) methyl] - 5-Methoxycarbonylmethylidenedianaphthene (prepared as described in Example 28) was hydrolyzed with sodium hydroxide, and the product was recrystallized from a mixture of ethanol and diethyl ether to give 0.20 g of the title compound as a pale yellow powder, melting at 233-235 ° C (dec).

Example 30 30

Methyl 2 - [(1-imidazolyl) -2,2-dimethylpropyl] - 6,7-dihydrothia-naphthene-5-carboxylate Using the same procedure as described in Example 22, 0.95 g of the title compound was obtained as a pale brown oily substance from 1.05 g. methyl 2- (2,2-dimethyl-1-hydroxypropyl) -6,7-dihydrothianaphthene-5-carboxylate.

«95252 71

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 1.06 (9H, singlet); 3.80 (3H, singlet); 6.91 (1H, singlet).

5

Example 31

Sodium 5- (6,7-dihydro-2-yl - (1-imidazolyl) -2,2-dimethylpropylthianaphenylcarboxylate 3/2 hydrate 10 Using the same procedure as described in Example 19, 0.95 g of methyl 2- [1- (1-imidazolyl) ) - 2,2-dimethylpropyl] -6,7-dihydrothianaphthene-5-carboxylate was hydrolyzed and the product was reprecipitated from a mixture of methanol and diethyl ether to give 0.71 g of the title compound as a colorless amorphous powder.

Infrared Absorption Spectrum (Nujol Mull) u ^ cin'1: 1620, 1560.

20 Elemental analysis:

Calculated for C17H19N2O2SNa. For 3/2 H 2 O: C, 55.88%; H, 6.07%; N, 7.67%; S, 8.77%

Found: C, 55.56%, H, 5.76%, N, 7.24%; S, 8.62%.

’25 Example 32

Methyl 6,7-dihydro-2 - [(cyclohexyl) (1-imidazolyl) methyl] thianaphthene-5-carboxylate Using the same procedure as described in Example 22, 0.41 g of the title compound was obtained as a pale brown oily substance from 1.42 g of methyl 6,7-dihydro-2 - [(cyclohexyl) (hydroxy) methyl ] -thianaphthene-5-carboxylate (prepared as described in Preparation 25).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.77 (3H, singlet).

35 72

Example 33 95252

Sodium 5- {6,7-dihydro-2 - [(cyclohexyl) (1-imidazolylmethyl] thianaphthene] carboxylate 3/2 hydrate 5 Using the same procedure as described in Example 19, 0.41 g of methyl 6,7-dihydro-2- [ (cyclohexyl) (1-imidazolyl) methyl] thianaphthene-5-carboxylate (prepared as described in Example 32), and the product was reprecipitated from a mixture of methanol and diethyl ether to give 0.25 g of the title compound as a colorless amorphous powder.

Infrared Absorption Spectrum (Nujol Mull) umaxcm'1: 1625, 1560.

15

Elemental analysis:

Calculated for C 18 H 21 N 2 O 2 SNa. 3 / 2H 2 O: C, 58.30%, H, 6.18%; N, 7.16%; S, 8.19%.

Found: C, 58.39%; H, 6.19%; N, 6.92%; S, 8.31%.

20

Example 34

Methyl 4.5.6.7-tetrahydro-2-yl (cyclohexyl) (1-imidazolylmethyl) thianaphthene-5-carboxylate • .......... · '25 Using the same procedure as described in Example 22, 0.39 g was obtained. the title compound as a pale brown oily substance from 0.52 g of methyl 4,5,6,7-tetrahydro-2 - [(cyclohexyl) (hydroxy) methyl] thianaphthenecarboxylate [prepared in the same manner as described in Example 24 (a), but starting from methyl 2- [* formyl-6-7-dihydrothianaphthene-5-carboxylate].

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.70 (3H, singlet); 35 6.63 (1H, singlet).

• I

11 73

Example 35 95252 5- (4.5.6.7-Tetrahydro-2 - [(cyclohexyl) (1-imidazolyl) methyl] thia-naphthenic carboxylic acid Dohydrochloride hydrate 5 Using the same procedure as described in Example 21, 0.38 g of methyl 4.5.6 was hydrolyzed. , 7-tetrahydro-2 - [(cyclohexyl) (1-imidazolyl) methyl] thianaphthene-5-carboxylate and the product was recrystallized from a mixture of methanol and diethyl ether to give 0.19 g of the title compound as colorless needles, melting at 202-204 ° C. .

Elemental analysis:

Calculated for C 18 H 24 N 2 O 2 S. HC1. H2O and lie: C, 57.20%; H, 6.82%; N, 7.02%; S, 8.05%; Cl, 8.89%.

Found: C, 56.77%; H, 6.69%; N, 7.45%; S, 8.25%; Cl, 9.10%.

Example 36

Methyl 5- (1-imidazolylmethyl) -5,6,7-tetrahydrothianaphthene-2-carboxate

A solution of 0.35 g of imidazole in 10 ml of dimethylformamide was added dropwise at room temperature to a suspension of 0.12 g of sodium hydride (55% by weight as a mineral oil suspension) in 10 ml of dimethylformamide under a nitrogen atmosphere. After 30 minutes, a solution of 0.78 g of methyl 5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate (prepared as described in Preparation 46) in 20 ml of dimethylformamide was added dropwise, and the mixture was allowed to react. 2 hours while heating at 50 ° C. After this time. The reaction mixture was poured into ice water containing 0.17 ml of glacial acetic acid.

The mixture was then adjusted to pH 8 by the addition of aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue 35 was subjected to silica gel column chromatography, eluting with a 20: 1: 1 by volume mixture of ethyl acetate, ethanol and triethylamine to give 0.49 g of the title compound as an oily substance.

74 95252

Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 3.85 (3H, singlet); 3.95 (2H, doublet, J = 6.0 Hz); 6.85-7.6 (4H, multiplet).

5

Example 37 2- (5- (D-Imidazolyl) methyl-4,5,6,7-tetrahydrothianaphthalenecarboxylic acid hydrochloride 0.47 g of methyl 5- (1-imidazolylmethyl) -4,5,6,7-tetrahydrothianaphthene-2 carboxylate (prepared as described in Example 36) was dissolved in a mixture of glacial acetic acid and concentrated hydrochloric acid, 5 ml each, and the mixture was heated at reflux for 6 hours. After this time, the reaction mixture was evaporated to dryness under reduced pressure, and the resulting residue was reprecipitated from a mixture of isopropyl alcohol and diethyl ether to give 0.47 g of the title compound as a colorless, amorphous powder.

20 Infrared Absorption Spectrum (KBr) umaxcnf :: 1680.

Elemental analysis: Calculated for C 13 H 11 N 2 O 2 S.HCl: 25 C, 52.26%; H, 5.06%; N, 9.38%; S, 10.73%; Cl, 11.87%.

Found: C, 52.38%; H, 5.13%; N, 9.16%; S, 10.55%; Cl, 12.01%.

Example 38 Methyl 5-Cl-imidazolyl) methyl 6,7-dihydrothianaphthene-2-carboxylate Using the same procedure as described in Example 36, 0.39 g of the title compound was obtained as an oily substance from 0.63 g of methyl 5-35 methanesulfonyloxymethyl-6,7-dihydrothianaphthene-2-carboxylate (prepared as described in Preparation 34).

75 95252

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.88 (3H, singlet); 4.63 (2H, singlet); 6.5-7.6 (5H, multiplet).

5

Example 39 2- {5- (1-Imidazolyl) methyl-6,7-dihydrothianaphthene-carboxylic acid hydrochloride 10 Using the same procedure as described in Example 37, 0.27 g of the title compound was obtained as a colorless amorphous powder from 0.31 g of methyl 5- (1 -imidazolyl) methyl 6,7-dihydrothianaphthene-2-carboxylate (prepared as described in Example 38).

15

Infrared Absorption Spectrum (Nujol Mull) 1690.

Elemental analysis: 20 Calculated for C13H12N2O2S. HCl: C, 52.61%; H, 4.42%; N, 9.44%; S, 10.80%; Cl, 11.95%. Found: C, 52.77%; H, 4.44%; N, 9.20%; S, 11.03%; Cl, 12.01%.

Example 40 *! 25

Methyl 6- (1-imidazolyl) methyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate Using the same procedure as described in Example 36 was obtained. 0.87 g of the title compound as a colorless amorphous powder from 1.00 g of methyl 6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate (prepared as described in Preparation 38).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 35 3.83 (3H, singlet); 3.96 (2H, doublet, J = 6.0 Hz); 6.9-7.6 (4H, multiplet).

2- [6- (1-Imidazolyl) naphthyl-4,5,6,7-tetrahydrothianaphenylcarboxylic acid hydrochloride 5 76

Example 41 95252 Using the same procedure as described in Example 37, 0.51 g of the title compound was obtained as a colorless, amorphous powder from 0.74 g of 6- (1-imidazolyl) methyl 4,5,5,7-tetrahydrothianaphthene-2-carboxylate ( prepared as described in Example 40).

10

Infrared Absorption Spectrum (Nujol Mull) υ ^ οπΓ1: 1685.

Elemental analysis: Calculated for C13HuN2O2S. HCl: C, 52.26%; H, 5.06%; N, 9.38%; S, 10.73%; Cl, 11.87%. Found: C, 52.03%; H, 4.99%; N, 9.53%; S, 10.71%; Cl, 11.72%.

Example 42 20

Methyl 6- (1-imidazolyl) methyl-4,5-dihydrothianaphthene-2-carboxylate Using the same procedure as described in Example 36, 0.29 g of the title compound was obtained as a colorless amorphous powder from 0.35 g of methyl 6-methanesulfonyloxymethyl-4, 5-dihydrothianaphthene-2-carboxylate (prepared as described in Preparation 42).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.84 (3H, singlet); 4.68 (2H, singlet); 6.5-7.6 (5H, multiplet).

Li 2- [6- (1-Imidazolyl) methyl-4,5-dihydrothianaphthene] carboxylic acid hydrochloride 5 77

Example 42 95252 Using the same procedure as described in Example 37, 0.23 g of the title compound was obtained as a colorless amorphous powder from 0.29 g of methyl 6- (1-imidazolyl) methyl 4,5-dihydrothianaphthene-2-carboxylate (prepared as described in Example 42).

10

Infrared Absorption Spectrum (KBr) ν cm -1: 1690.

Elemental analysis: 15 Calculated for C13H12N2O2S. HCl: C, 52.61%; H, 4.42%; N, 9.44%; S, 10.80%; Cl, 11.95%. Found: C, 52.40%; H, 4.32%; N, 9.60%; S, 10.59%; Cl, 11.88%.

Example 44 20

Methyl 5- {2- (1-imidazolyl) ethyl -4,5,6,7-tetrahydrothianaphthene-2-carboxylate Using the same procedure as described in Example 36, 1.28 g of the title compound was obtained as an oily substance from 1.50 g of methyl 5-methanesulfonyloxymethyl. -4,5,6,7-tetrahydrothianaphthene-2-carboxylate (prepared as described in Preparation 30).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.90 (3H, singlet); 4.05 (2H, triplet, J = 6.5Hz); 6.9-7.6 (4H, multiplet).

Example 45 2- <5- {2- (1-Imidazolvyl) ethyl] -4,5,6,7-tetrahydrothianaphthylylcarboxylic acid hydrochloride 5 78 95252 Using the same procedure as described in Example 37, 0.27 g of the title compound was obtained as a colorless amorphous powder 1.00 g from methyl 5- [2- (1-imidazolyl) ethyl] -4,5,6,7-tetrahydrothianaphthene-2-carboxylate (prepared as described in Example 44).

10

Infrared Absorption Spectrum (KBr) ν max: 1: 1690.

Elemental analysis: Calculated for C 14 H 16 N 2 O 2 S.HCl: C, 53.76%; H, 5.48%; N, 8.96%; S, 10.25%; Cl, 11.33%. Found C, 53.70%; H, 5.51%; N, 9.13%; S, 10.39%; Cl, 11.27%.

Preparation 1 20

Methyl 4,5-dihydrothianaphthene-6-carboxylate

A solution of 20 g of 4,5,6,7-tetrahydro-7-ketothianaphthene in dimethylformamide was added dropwise to a suspension of 6.31 g of sodium hydride (55% by weight as a mineral oil suspension) in 100 ml of dimethylformamide at room temperature. and the mixture was stirred for 10 minutes. Then, 33 ml of dimethyl carbonate was added dropwise to the reaction mixture at 5 ° C, and the reaction mixture was stirred for 90 minutes. It was then poured into a mixture of ice water and 8.7 ml of glacial acetic acid, and filtered. The precipitate was collected to give 31.6 g of a crude product containing methyl 4,5,6,7-tetrahydro-4-oxothianaphthene-6-carboxylate. A solution of this crude product in a mixture of tetrahydrofuran and methanol (100 ml each) was cooled to -15 ° C and 4.98 g of sodium borohydride was added over one hour. After this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was extracted; a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. The extract was washed 5-6 times with water, dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 500 ml of benzene, 2.5 g of n-toluenesulfonic acid was added to the solution, and the mixture was subjected to azeotropic distillation by heating for 30 minutes to remove the resulting water. After this time, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, filtered and concentrated by evaporation under reduced pressure. The product was subjected to silica gel column chromatography using a 1: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 20.1 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.80 (3H, singlet); 6.86 & 7.29 (1H each, both doublets, J = 5.0 Hz); Δ 7.54 (1H, singlet).

Preparation 2

Methyl 2-formyl-4,5-dihydrothianaphthene-6-carboxylate 30 ml of a solution of 7.5 g of 4,5-dihydrothianaphthene-6-carboxylate were added dropwise to a suspension of 10.3 g of aluminum chloride in 50 ml of methylene chloride. At -10 ° C under a nitrogen atmosphere. After 10 minutes, a solution of 5.24 ml of dichloro-25-methyl ether in 30 ml of methylene chloride was added dropwise over one hour, and the reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and then the resulting solution was washed alternately with saturated aqueous sodium bicarbonate solution and aqueous sodium chloride solution. It was then dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 8.21 g of the title compound as an oily substance.

35 Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: ··; 3.83 (3H, singlet); 80 95252 7.50 & 7.57 (1H each, both singlets); 9.86 (1H, singlet).

Preparation 3 5

Methyl 2-benzovyl-4,5-dihydrothianaphthene-6-carboxylate Using the same procedure as described in Preparation 2, 1.65 g of the title compound were obtained as an oily substance from 1.78 g of aluminum chloride, 1.17 ml of benzoyl chloride and 1.30 ml of: methyl 4,5-dihydrothianaphthene-6-carboxylate.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.81 (3H, singlet).

15

Preparation 4

Methyl 4,5,6,7-tetrahydrothianaphthene-6-carboxylate 1.63 g of methyl 4,5-dihydrothianaphthene-6-carboxylate was subjected to catalytic reduction in the presence of 10% by weight of palladium on carbon (1.6 g) under a hydrogen atmosphere while shaking the solution for 4 hours. for an hour. After this time, the reaction mixture was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography using a 10: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 1.31 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.73 (3H, singlet); 6.75 & 7.08 (2H each, both doublets, J = 5.0Hz).

Preparation 5

Methyl 2-formyl-4.5,6,7-tetrahydrothianaphthene-6-carboxylate Using the same procedure as described in Preparation 2, 0.3 g of the title compound was obtained as an oily substance from 0.50 g of methyl 4,5,6,7-

II

81 95252 te trhydro thianaphthene-6-carboxylate (prepared as described in Preparation 4).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: δ 3.73 (3H, singlet); 7.45 (1H, singlet); 9.83 (1H, singlet).

Preparation 6 10 4.5.6.7- Tetrahydro-6-methoxycarbonylmethylidene thianaphthene

A solution of 9.57 g of 4,5,6,7-tetrahydro-7-ketothianaphthene in 30 ml of dimethylformamide was added dropwise to a suspension of 3.29 g of sodium hydride (55% by weight as a suspension in mineral oil) in 30 ml. dimethylformamide under a nitrogen atmosphere. The mixture was cooled to 5 ° C, dimethyl carbonate was added dropwise, and the mixture was stirred at room temperature for 1 hour. A solution of 6.6 ml of methyl bromoacetate in 10 ml of dimethylformamide was then added and the mixture was stirred at room temperature for one hour. After this time, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution and concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was washed alternately with water, saturated aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The washed solution was then dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure, the residue was dissolved in a mixture of concentrated hydrochloric acid and glacial acetic acid of 200 ml each, and the solution was heated under reflux for 3 hours. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in 500 ml of methanol and 2 ml of concentrated sulfuric acid, and the reaction mixture was heated again under reflux for 2 hours. After this time, the product was concentrated by evaporation under reduced pressure. The residue was extracted with a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. The extract was washed 5-6 times with water, dried over anhydrous sodium sulfate, filtered and concentrated. by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 10.13 g of 4,5,6,7-tetrahydro-7-keto-6-methoxycarbonylmethylthianaphthene as an oily substance.

2.0 g of sodium laboratory hydride was added to a solution of 10.13 g of the ketone thus prepared in 200 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. After this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was extracted with a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. The extract was washed 5-6 times with water, dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue was acetylated with 20 ml of acetic anhydride in 40 ml of pyridine. 0.7 g of j-toluenesulfonic acid monohydrate was added to a solution of the acetylated product in 250 ml of toluene and the mixture was heated at reflux for 30 minutes. After this time, the product was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, filtered and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using a 5: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 5.50 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppnt: 3.65 (3H, singlet); Δ 6.34 (1H, singlet).

Preparation 7 2-Formyl-4.5.6.7-tetrahydro-6-methoxycarbonylmethylidene thianaphthene 30 ♦ «* Using the same procedure as described in Preparation 2, 1.50 g of the title compound was obtained as an oily substance from 2.50 g of 4,5,6,7-tetra -hydro-6-methoxycarbonylmethylidene thianaphthene (prepared as described in Preparation 6).

35. Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.72 (3H, singlet);

II

83 95252 6.33 (1H, singlet); 7.40 (1H, singlet); 9.81 (1H, singlet).

5 Preparation 8

Ethyl 6- (4S-dihydrothianaphthene) carboxylate 8 (a) A solution of 57 ml of tin tetrachloride in 600 ml of methylene chloride was cooled to -35 ° C and a solution of 60 g of ethyl 4- (3- thienyl) butyrate in 600 ml of methylene chloride under nitrogen for one hour After 20 minutes of dropwise addition, a solution of 35 ml of dichloromethyl methyl ether in 600 ml of methylene chloride was added dropwise to the resulting mixture over one hour while maintaining the mixture at -35 ° C: After stirring for another hour, the reaction mixture was treated in the usual manner to give a syrupy substance containing 4- [3- (2-formyl) thienyl] butyrate.

(B) 18.5 ml of ethanol was added dropwise to a suspension of 13.86 g of sodium hydride (55% by weight as a mineral oil suspension) in 500 ml of toluene under a nitrogen atmosphere at room temperature, and the resulting mixture was then heated to 80 ° C. A solution of the syrupy substance [obtained as described in step (a) above) in 250 ml of toluene was added all at once and the resulting mixture was allowed to cool to room temperature.

When the reaction mixture was cold, it was treated in the usual manner to give a syrupy substance, which was then distilled under reduced pressure to give 32.80 g of the title compound, which boiled at 125-128 ° C / 2 mmHg (266 Pa).

30

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 1.31 (triplet, 7Hz); 4.24 (7Hz, quartet); 6.89 & 7.29 (each doublet, 5Hz); 35 7.54 (singlet).

Methyl 6.7-dihydrothianaphthene-5-carboxylate 84

Preparation 9 95252 A solution of 20 g of 4,5,6,7-tetrahydro-4-ketothianaphthene in dimethylformamide was added dropwise at room temperature to a suspension of 6.31 g of sodium hydride (55% by weight as a mineral oil suspension) in 100 ml of dimethylformamide. and the mixture was stirred for 10 minutes. 33 ml of dimethyl carbonate was added dropwise at 5 ° C to the above reaction mixture 10, and then the mixture was stirred for 90 minutes. The reaction mixture was then poured into a mixture of ice water and 8.7 ml of glacial acetic acid, and the mixture was filtered to give 31.6 g of a crude product containing methyl 4,5,6,7-tetrahydro-4-ketothianaphthene-5-carboxylate. A solution of the crude product in a mixture of tetrahydrofuran and methanol (100 ml each) was cooled to -15 ° C and 4.98 g of sodium borohydride was added over one hour. After this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and then concentrated by evaporation under reduced pressure. The residue was then dissolved in 500 ml of benzene. 2.5 g of j-toluenesulfonic acid monohydrate was added thereto, and the mixture was subjected to azeotropic distillation by heating for 30 minutes to remove the resulting water. After this time, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 1: 1 by volume mixture of hexane and ethyl acetate as the eluent to give 20.1. 30 g of the title compound as an oily substance.

• «

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.78 (3H, singlet); 6.93 & 7.8 (1H each, both doublets, J%, 0Hz); 35 7.52 (1H, singlet).

11

• I

Methyl 2-formyl-6,7-dihydrothianaphthene-5-carboxylate 85

Preparation 10 95252 A solution of 7.5 g of methyl 6,7-dihydrothianaphthene-5-carboxylate (prepared as described in Preparation 9) in 30 ml of methylene chloride was added dropwise at -10 ° C to a suspension of 10.3 g of aluminum chloride in 50 ml of methylene chloride under a nitrogen atmosphere, after 10 minutes, a solution of 5.24 ml of dichloromethyl methyl ether in 30 ml of methylene chloride was added dropwise over one hour, and the reaction mixture was poured into ice water and stirred for 1 hour. The mixture was then extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and hexane to give 8.21 g of the title compound as pale red needles, melting at 125-127 ° C.

Preparation 11 20

Methyl 2-acetyl-6,7-dihydrothianaphthene-5-carboxylate

A solution of 2.0 methyl 6,7-dihydrothianaphthene-5-carboxylate (prepared as described in Preparation 9) in 30 ml of methylene chloride was added dropwise at -10 ° C to a suspension of 2.75 g of aluminum chloride. In 30 ml of methylene chloride. After 10 minutes, a solution of 1.10 ml of acetyl chloride in 10 ml of methylene chloride was added over 30 minutes. After this time, the reaction mixture was treated as described in Preparation 10 by pouring into ice water to concentrate it, and the resulting residue was subjected to silica gel column chromatography using a 3: 1 by volume mixture of hexane and ethyl acetate as the eluent. The product was then recrystallized from a mixture of ethyl acetate and hexane to give 2.25 g of the title compound as pale yellow needles, melting at 116-118 ° C.

35

Methyl 2-benzoyl-6,7-dihydrothianaphthene-5-carboxylate 86

Preparation 12 95252 Using the same procedure as described in Preparation 11, 1.78 g of aluminum chloride, 1.17 ml of benzoyl chloride and 1.30 g of methyl 6,7-dihydrothianaphthene-5-carboxylate (prepared as described in Preparation 9) were reacted among themselves. The reaction mixture was treated as described in Preparation 10 from draining to ice water to concentration, and the resulting residue was subjected to silica gel column chromatography using a 4: 1 by volume mixture of hexane and ethyl acetate as the eluent. The product was then recrystallized from a mixture of ethyl acetate and hexane to give 1.65 g of the title compound as colorless needles, melting at 99-101 ° C.

15

Preparation 13

Methyl 6,7-dihydro-2- (2-methoxyvinyl) thianaphthene-5-carboxylate A solution of 3.48 g of methyl 2-formyl-6,7-dihydrothianaphthene-5-carboxylate (prepared as described in Preparation 10) In 30 ml of tetrahydrofuran was added dropwise to an ether solution of ylide prepared from 13.42 g of methoxymethyltriphenylphosphoridene chloride and 19.0 ml of a 15% w / w solution of butyllithium in hexane under a nitrogen atmosphere. After this time, the reaction mixture was poured into ice water and extracted with diethyl ether. The extract was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using a mixture of hexane and ethyl acetate as the eluent to give 1.0 g of the title compound as an oily substance.

»

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.60 & 3.73 (6H, each singlet).

35 ml of 2- (5-methoxycarbonyl-6,7-dihydrothianaphthyl) acetaldehyde 87

Preparation 14 95252 5 A solution of 1.0 g of methyl 6,7-dihydro-2- (2-methoxyvinyl) thia-naphthene-5-carboxylate (prepared as described in Preparation 13) in a mixture of 30 ml of 1 p / t-% hydrochloric acid and 60 ml of acetone, was heated at reflux for 9 hours. The solvent was removed from the reaction mixture under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. It was then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 0.24 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 9.90 (1H).

20

Preparation 15

Methyl 6,7-dihydro-2- (2-hydroxyethyl) thianaphthene-5-carboxylate 42 mg of sodium borohydride were added to a solution of 0.24 g of 2- (5-methoxycarbonyl-6,7-dihydrothianaphthyl) acetaldehyde (prepared as described in Preparation 14) in a mixture of methanol and tetrahydrofuran (10 ml each). After this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 3: 2 by volume mixture of hexane and ethyl acetate as an eluent to give 0.17 g of the title compound as an oily substance.

»· 88 95252

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.80 (3H, singlet); 6.73 (1H, singlet): 7.45 (1H, singlet).

5

Preparation 16

Methyl 2- (2-methanesulfonylmethylethyl) -6,7-dihydrothianaphthene-5-carboxylate 10

A solution of 0.08 ml of methanesulfonyl chloride in 3 ml of diethyl ether was added to a solution of 0.17 g of methyl 6,7-dihydro-2- (2-hydroxyethyl) thianaphthene-5-carboxylate (prepared as described). in Preparation 15) in a mixture of 5 ml of diethyl ether and 0.30 ml of triethylamine, and the mixture was stirred at room temperature for 30 minutes. After this time, the reaction mixture was poured into ice water, and the mixture was extracted with diethyl ether. The extract was washed successively with saturated aqueous sodium bicarbonate solution and aqueous sodium chloride solution. It was then dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 0.19 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 2.97 (3H, singlet); 3.78 (3H, singlet).

Preparation 17 30 4.5.6.7-Tetrahydro-4-keto-5- (methoxycarbonylmethyl) thianaphthene

A solution of 9.57 g of 4,5,6,7-tetrahydro-4-ketothianaphthene in 30 ml of dimethylformamide was added dropwise to a suspension of 3.29 g of sodium hydride (55% by weight as a mineral oil suspension) in 30 ml. dimethylformamide under a nitrogen atmosphere. The mixture was cooled to 5 ° C, 16 ml of dimethyl carbonate was added thereto, and the mixture was stirred at room temperature under 89 95252 for one hour. A solution of 6.6 ml of methyl bromoacetate in 10 ml of dimethylformamide was added and the mixture was stirred for one hour. After this time, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The residue was dissolved in a mixture of 200 ml of concentrated aqueous hydrochloric acid and glacial acetic acid, and the solution was heated under reflux for 3 hours. The reaction mixture was then evaporated to dryness under reduced pressure, and the residue was dissolved in a mixture of 500 ml of methanol and 2 ml of concentrated sulfuric acid. The solution was heated at reflux for 2 hours. After this time, the solvent was removed by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 10.13 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.72 (3H, singlet); 7.06 & 7.38 (1H each, both doublets, J-6.0Hz).

Preparation 18 4.5.6.7-Tetrahydro-5- (methoxycarbonylmethylidene) thianaphthene 2.0 g of sodium borohydride was added to a solution of 10.13 g of 4.5.6.7-tetrahydro-4-keto-5- (methoxycarbonylmethyl) thianaphthene 30 (prepared as is described in Preparation 17) in 200 ml of methanol and the mixture was stirred at room temperature for 30 minutes. After this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and then concentrated by evaporation under reduced pressure. Residue. dried thoroughly under reduced pressure and then acetylated with 20 ml of acetic anhydride in 40 ml of pyridine. After this time, the 90 95252 reaction mixture was concentrated by evaporation under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solution was washed alternately with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. It was then filtered and concentrate 5 was evaporated under reduced pressure. The resulting residue was dissolved in 250 ml of toluene, and the solution was heated under reflux in the presence of β-toluenesulfonic acid monohydrate (0.7 g) for 30 minutes. After this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 5: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 5.50 g of the title compound as an oily powder.

15

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.17 (2H, singlet); 3.67 (3H, singlet); 6.31 (1H, singlet).

20

Preparation 19 1-Form-4,5-7,7-tetrahydro-5- (methoxycarbonylmethylidene) thianaf -. earn 25

Following the same procedure as described in Preparation 10, 1.50 g of the title compound was obtained as an oily substance from 2.50 g of 4,5,6,7-tetrahydro-5- (methoxycarbonylmethylidene) thianaphthene (prepared as described in Preparation 17). .

30

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.70 (3H, singlet); 6.29 (1H, singlet); 7.40 (1H, singlet); 35 9.75 (1H, singlet).

91

Preparation 20 95252 4.5.6.7-Tetrahydro-2-hydroxymethyl-5-methoxycarbonylmethylidene) -thianaphthene 5 0.26 g of sodium borohydride was added to a solution of 1.47 g of 2-formyl-4,5,6,7-tetrahydro-5- (methoxycarbonylmethylidene) thianaphthene (prepared as described in Preparation 19) in a mixture of methanol and tetrahydrofuran (30 ml each). After this time, the reaction mixture 10 was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and then concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using a 3: 2 by volume mixture of hexane and ethyl acetate to give 1.24 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.69 (3H, singlet); 6.24 (1H, singlet); 6.67 (1H, singlet).

Preparation 21 25 Methyl 2-trimethylacetyl-6,7-dihydrothianaphthene-5-carboxylate Using the same procedure as described in Preparation 11, 1.47 g of the title compound were obtained as an oily substance using 3.8 g of aluminum chloride, 3.0 g of methyl 6,7-dihydrothianaphthene. -5-carboxylate (val-30 subordinated as described in Preparation 9) and 2.7 ml of pivaloyl chloride.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 1.40 (9H, singlet); 35 3.82 (3H, singlet); ; 7.62 (1H, singlet).

92

Preparation 22 95252

Methyl 2- (2,2-dimethyl-1-hydroxyethyl) -6,7-dihydrothianaphthene-5-carboxylate Using the same procedure as described in Preparation 15, 1.05 g of the title compound was obtained as an oily substance from 1.47 g of methyl 2-trimethylacetyl. -6,7-dihydrothianaphthene-5-carboxylate (prepared as described in Preparation 14).

10

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 0.95 (9H, singlet); 3.75 (3H, singlet); 6.65 (1H, singlet).

15

Preparation 23

Methyl 2-cyclohexylcarbonyl-6,7-dihydrothianaphthene-5-carboxylate Using the same procedure as described in Preparation 11, 2.79 g of the title compound were obtained as an oily substance using 2.56 g of aluminum chloride, 2.0 g of methyl 6,7-dihydrothianaphthene. -5-carboxylate (prepared as described in Preparation 9) and 1.93 ml of cyclohexane-carbonyl chloride.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.83 (3H, singlet); 7.52 (1H, singlet); Δ 7.58 (1H, singlet).

II

93

Preparation 24 95252

We twig -cyclohexylcarbonyl - 5-methoxycarbonyl -4. 5.6.7-Terahydrotyanaphthene-5-carboxylate 5 1.07 g of methyl 2-cyclohexylcarbonyl-6,7-dihydrothianaphthene-5-carboxylate (prepared as described in Preparation 23) in methanol was catalytically reduced in 1.10 g of 10 w / w% palladium on carbon in the presence of catalytic amounts of acetic acid and in a hydrogen-10 atmosphere. The reaction mixture was then adjusted to pH 8 by the addition of aqueous sodium bicarbonate solution. The resulting solution was filtered and the filtrate was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure to give 0.58 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.75 (1H, singlet); 7.43 (1H, singlet).

20

Preparation 25

Methyl 6,7-dihydro-2 - [(cyclohexyl) (hydroxy) methyl] thianaphthene-5-carboxylate Using the same procedure as described in Preparation 15, 1.42 g of the title compound were obtained as an oily substance from 1.72 g of methyl 2-cyclohexylcarbonyl - 6,7-dihydrothyanaphthene-5-carboxylate (prepared as described in Preparation 23).

30

Preparation 26

Methyl 4.5,6,7-tetrahydro-2 - [(cyclohexyl) (hydroxy) methyl] thianaphthene-5-carboxylate 35; Using the same procedure as described in Preparation 24, 0.52 g of the title compound was obtained as an oily substance from 0.58 g of methyl 6,7-94,925,252 dihydro-2 - [(cyclohexyl) (hydroxy) methyl] thianaphthene-5-carboxylate ( prepared as described in Preparation 25).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: δ 3.73 (3H, singlet); 6.60 (1H, singlet).

Preparation 27 10 5-Hydroxymethyl-4.5,6,7-tetrahydrothianaphthene

A solution of 3.20 g of methyl 4,5,6,7-tetrahydrothianaphthene-5-carboxylate in 35 ml of diethyl ether was added dropwise to a suspension of 0.62 g of lithium aluminum hydride in 30 ml of diethyl ether at 15 ° C: below. After 10 minutes, sodium sulfate decahydrate was added thereto, and the mixture was stirred. The reaction mixture was then filtered using Celite 545 filter aid (Celite is a trademark), and the filtrate was concentrated by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as an eluent to give 2.59 g of eluent.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.53 (2H, doublet); 25 6.68 & 7.00 (each 1H, both doublets, J-6.0Hz).

Preparation 28 5-Methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene 30

A solution of 1.00 ml of methanesulfonyl chloride in 10 ml of methylene chloride was added dropwise to a solution of 1.09 g of 5-hydroxymethyl-4,5,6,7-tetrahydrothianaphthene (prepared as described in Preparation 27) in a mixture. , containing 30 ml of methylene chloride and 2.71 35 ml of triethylamine with ice water while cooling.

11 • 95 95252

The mixture was then stirred at room temperature for 1 hour. After this time, the reaction mixture was poured into ice water and extracted with methylene chloride. The extract was washed successively with saturated aqueous sodium bicarbonate solution and aqueous sodium chloride solution. It was then dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel using a 3: 1 by volume mixture of hexane and ethyl acetate as the eluent to give 1.38 g of the title compound as an oily substance.

10

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 2.98 (3H, singlet): 4.16 (2H, doublet, J = 5.0Hz); 6.72 & 7.05 (1H each, both doublets, J = 5.0Hz).

15

Preparation 29 2-Formyl-5-methanesulfonyloxymethyl-4.5.6.7-tridrotianaphthene 20 A solution of 1.18 g of 5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrotianaphthene (prepared as described in Preparation 28) 35 per ml of methylene chloride was added dropwise to a suspension of 0.96 g of anhydrous aluminum chloride in 40 ml of methylene chloride at -30 ° C. in a nitrogen atmosphere. A solution of 0.54 ml of dichloromethyl methyl ether in 20 ml of methylene chloride was then added and the mixture was stirred at 0 ° C for 2 hours. After this time, the reaction mixture was poured into ice water, stirred for one hour and extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel using a 1: 1 by volume mixture of hexane and ethyl acetate as the eluent to give 0.85 g of the title compound as an oily substance.

35 Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.06 (3H, singlet); 4.24 (2H, doublet, J = 5.0 Hz); 96 95252 7.46 (1H, singlet); 9.85 (1H, singlet).

Preparation 30 5

Methyl 5-methanesulfonylloxymethyl-4.5.6,7-tetrahydrothianaphthene-2-carboxylate

A solution of 0.40 g of sodium chlorite in 5 ml of water was added dropwise at room temperature to a solution of 0.80 g of 2-formyl-5-methanesulfonyloxymethyl-4,5,6,7-trihydrothianaphthene (prepared as described in described in Preparation 29) and 1.77 g of sulfamic acid in 48 ml of a 5: 1 v / v mixture of dioxane and water. After the dropwise addition, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated by evaporation under reduced pressure and the resulting crude residue was dissolved in 150 any methanol. This solution was heated at reflux for 7 hours in the presence of a catalytic amount of concentrated sulfuric acid. After this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed alternately with water, aqueous sodium bicarbonate and aqueous sodium chloride. It was then dried over anhydrous sodium sulfate, filtered and concentrated by evaporation at 25 rpm under reduced pressure. The resulting residue was subjected to column chromatography through silica gel using a 3: 2 by volume mixture of hexane and ethyl acetate as an eluent to give 0.78 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.03 (3H, singlet); 3.86 (3H, singlet); 4.22 (2H, doublet); 7.48 (1H, singlet).

35 5-Hydroxymethyl-6,7-dihydrothianaphthene 97

Preparation 31 95252 Using the same procedure as described in Preparation 27, 1.65 g of the title compound were obtained as an oily substance from 2.07 g of methyl 6,7-dihydrothianaphthene-5-carboxylate.

Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 4.19 (2H, doublet, J = 6.0Hz); 6.41 (1H, triplet, J = 1.5 Hz); 6.81 & 7.03 (each 1H, both doublets, J = 5.0Hz).

Preparation 32 5-Methanesulfonylmethoxymethyl-6,7-dihydrothianaphthene Using the same procedure as described in Preparation 28, 1.07 g of the title compound was obtained as an oily substance from 1.14 g of 5-hydroxymethyl-6,7-dihydrothianaphthene (prepared as described in Preparation 31).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.02 (3H, singlet); 4.31 (2H, singlet) 6.45 (1H, J = 1.5 Hz); 6.85 & 7.06 (1H each, both doublets, J = 5.0 Hz).

Preparation 33 30 '2-Formyl-5-methanesulfonyl-methyloxymethyl-6,7-dihydrothianaphthene Using the same procedure as described in Preparation 29, 0.82 g of the title compound was obtained as an oily substance from 0.99 g of 5-methanesulfon-35-yloxymethyl-6,7-dihydrothianaphthene. prepared as described; in Preparation 32).

98 95252

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.07 (3H, singlet); 4.33 (2H, singlet); 6.46 (1H, triplet, J = 1.5 Hz); Δ 7.49 (1H, singlet); 9.89 (1H, singlet).

Preparation 34 10 Methyl 5-methanesulfonyloxymethyl-6,7-dihydrothianaphthene-2-carboxylate Using the same procedure as described in Preparation 30, 0.69 g of the title compound was obtained as an oily substance from 0.75 g of 2-formyl-5-15 methanesulfonyloxymethyl-6, 7-dihydrothianaphthene (prepared as described in Preparation 33).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.02 (3H, singlet); 3.88 (3H, singlet); 4.30 (2H, singlet); 6.43 (1H, triplet, J = 1.5 Hz); 7.50 (1H, singlet).

4 25 Preparation 35 6-Hydroxymethyl-4.5.6.7-tetrahydrothianaphthene Using the same procedure as described in Preparation 27, 3.91 g of the title compound was obtained as an oily substance from 4.85 g of methyl 4,5,6,7-tetrahydrotyanaphthene-6-carboxylate. (prepared as described in Preparation 4).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 35 3.57 (2H, doublet, J = 6.6 Hz); ; 6.69 & 7.00 (each 1H, both doublets, J = 5.0Hz).

6-Methanesulfonyloxymethyl-4.5.6,7-tetrahydrothianaphthene 99

Preparation 36 95252 Using the same procedure as described in Preparation 2, 4.28 g of the title compound was obtained as an oily substance from 3.50 g of 6-hydroxymethyl-4,5,6,7-tetrahydrothianaphthene (prepared as described in Preparation 35).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 2.98 (3H, singlet); 4.17 (2H, doublet, J = 6.0 Hz); 6.72 & 7.04 (each 1H, both doublets, J = 5.0Hz).

Preparation 37 2-Formyl-6-methanesulfonylmethoxymethyl-4.5.6.7-tetrahydrothianaphthene Using the same procedure as described in Preparation 29, 2.92 g of the title compound were obtained as an oily substance from 4.11 g of 6-methanesulfonyloxymethyl-4.5, 6,7-tetrahydrothianaphthene (prepared as described in Preparation 26).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.05 (3H, singlet); 4.24 (2H, doublet, J = 5.0 Hz); 7.46 (1H, singlet); 9.85 (1H, singlet).

30 Preparation 38

Methyl 6-methanesulfonylmethoxymethyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate 35 Using the same procedure as described in Preparation 30, 2.19 g of the title compound were obtained as colorless needles, melting at 188-191 ° C, from 2.32 g. 2-Formyl-6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene (prepared as described in Preparation 27).

100 95252 Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.05 (3H, singlet); 3.86 (3H, singlet); 4.20 (2H, doublet, J = 5.0 Hz; 7.48 (1H, singlet)).

10

Preparation 39 6-Hydroxymethyl-4,5-dihydrothianaphthene Using the same procedure as described in Preparation 27, 1.19 g of the title compound was obtained as an oily substance from 1.64 g of methyl 4,5-dihydrothianaphthene carboxylate.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 4.22 (2H, doublet, J = 6.0Hz); 6.43 (1H, triplet, J = 1.5 Hz); 6.71 & 7.02 (each 1H, both doublets, J = 5.0Hz).

Preparation 40 6-Methanesulfonyloxymethyl-4,5-dihydrothianaphthene Using the same procedure as described in Preparation 28, 0.82 g of the title compound was obtained as an oily substance from 1.03 g of 6-hydroxymethyl-4,5-dihydrothianaphthene (prepared as described in Preparation 28). 39).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.01 (3H, singlet) δ 4.33 (2H, singlet) 6.48 (1H, triplet, J - 1.5z); 6.81 & 7.06 (1H each, both doublets, J = 5.0 Hz).

2-Formyl-6-methanesulfonyl moiety -4,5-dihydrothianaphthene 101

Preparation 41 95252 Using the same procedure as described in Preparation 29, 0.49 g of the title compound was obtained as an oily substance from 0.73 g of 6-methanesulfonyloxymethyl-4-5-dihydrothianaphthene (prepared as described in Preparation 40).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.05 (3H, singlet); 4.31 (1H, singlet); 6.47 (1H, triplet, J = 1.5 Hz); 7.50 (1H, singlet); Δ 9.88 (1H, singlet).

Preparation 42

Methyl 6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene-2-carboxylate Using the same procedure as described in Preparation 30, 0.39 g of the title compound was obtained as an oily substance from 0.40 g of 2-formyl-6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene. (prepared as described in Preparation 41).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.02 (3H, singlet); 3.87 (3H, singlet); Δ 4.29 (2H, singlet); 6.42 (1H, triplet, J = 1.5 Hz); 7.49 (1H, singlet).

Preparation 43 5- (2-Hydroxyethyl--4,5,6,7-tetrahydrothianaphthene 102 95252) Using the same procedure as described in Preparation 27, 3.75 g of the title compound were obtained as an oily substance from 4.50 g of 5-methoxycarbonylmethyl-4.5, 6,7-tetrahydrothianaphthene.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: δ 3.85 (2H, quartet, J = 6.5 Hz); 6.68 & 7.00 (each 1H, both doublets, J-6.0Hz).

Preparation 44 5- (2-Methanesulfonyloxyethyl) -4.5.6.7-tetrahydrothianaphthene Using the same procedure as described in Preparation 28, 3.72 g of the title compound were obtained as an oily substance from 3.68 g of 5- (2-hydroxyethyl) -4, 5,6,7-tetrahydrothianaphthene (prepared as described in Preparation 43).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 2.91 (3H, singlet); 4.25 (2H, triplet, J = 6.0 Hz); 25 6.73 & 7.07 (1H each, both doublets, J = 5.0 Hz).

Preparation 45 5- (2-Methanesulfonyloxyethyl) -2-formyl-4.5,6,7-tetrahydrothianaf-30ene Using the same procedure as described in Preparation 29, 2.29 g of the title compound were obtained as an oily substance from 3.51 g of 5- (2- methanesulfonyloxyethyl) -4,5,6,7-tetrahydrothianaphthene (prepared as described in Preparation 44).

n 103 95252

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.06 (3H, singlet); 4.19 (2H, triplet, J = 6.5 Hz); 7.44 (1H, singlet); Δ 9.88 (1H, singlet).

Preparation 46

Methyl (2-methanesulfonyloxyethyl) -4,5,6,7-tetrahydrothianaphthene-10 2-carboxylate Using the same procedure as described in Preparation 30, 1.93 g of the title compound were obtained as an oily substance from 2.13 g of 5- (2-methanesulfonyloxyethyl) -. 2-formyl-4,5,6,7-tetrahydrothianaphthene (prepared as described in Preparation 45).

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ ppm: 3.04 (3H, singlet); 3.88 (3H, singlet); 4.19 (2H, triplet, J = 6.5 Hz); 7.50 (1H, singlet).

Experiment 1 • 25 Inhibition of thromboxane A-> synthetase

The platelet microsome fraction was separated from rabbit and human blood by the method of Needleman et al [Needleman et al., Science, 193, 163 (1976)].

30

The activity of microsomal TXA2 synthetase in the presence of various compounds of the invention at various concentrations was determined by the modified method of Kayama et al. for one minute at 22 ° C, to a final volume of 0.2 ml. The reaction was quenched by the addition of 50 μΜ of 0.2M citric acid and then the mixture was extracted with 1.5 ml of ethyl acetate. The extract was concentrated by evaporation under a stream of nitrogen gas and then subjected to silica gel thin layer chromatography. The developing solvent for chromatography was a mixture of chloroform, methanol, acetic acid and water in a volume ratio of 90: 8: 1: 0.8. The inhibitory activity of the test compound was assessed by the decrease in the radioactivity of the TBX2 fraction (TXA2 is hydrolyzed to the more stable TXB2). The results are shown in the following Tables 1 and 2 as the IC50, i.e. the concentration required to inhibit thromboxane synthetase activity by 50%.

In addition to the compounds of the invention, we tested the activity of the known compound Dazoxiben, a substance systematically named 4- [2- (1-imidazolyl) ethoxy] benzoic acid hydrochloride and disclosed in GB Patent Publication No. 2038821. The compounds of the invention used were as follows: 15

Compound A - 4,5,6,7-Tetrahydro-2- (1-imidazolyl) methylthianaphthene-6-carboxylic acid hydrochloride (Compound No. 1-1 hydrochloride);

Compound B - Sodium 4,5-dihydro-2- (1-imidazolyl) methylthianaphthene-6-20 carboxylate (Sodium salt of Compound No. 2-1);

Compound C = 4,5,6,7-tetrahydro-2- (1-imidazolyl) methylthianaphthene-5-carboxylic acid hydrochloride (Compound No. 3-1 hydrochloride).

* <25 Results using rabbit platelet microsomes are given in Table 1, while results using human platelet microsomes are given in Table 2.

il 105 95252

table 1

Test compound IC50 (x 10'8M) 5 _ A 2.6 B 1.3 C 8.6 10 Dazoxibene 10.6

Table 2 15 _

Test compound IC50 (x 10'8M) A 3.0 20 B 3.1

Dazoxibene 76 As can be seen from the above results, the compounds of the invention show significantly higher activity than the known compound Dazoxibene and, in particular, as shown in Table 2, the activity of the compounds of the invention against thromboxane synthetase from human platelet microsomes is about 20-fold. 30 higher than the activity of Dazoxibem.

106 95252

Test 2

Antithrombotic activity in rabbits This test was performed by the modified method of Silver et al [Science, 183, 1085 (1974)]. The experimental animals used were male Japanese white rabbits weighing about 3 kg.

Each group of rabbits was orally administered the test compound in an appropriate dose of 10 and then, one hour after dosing, each was given 1.3 mg / kg of arachidonic acid by intravenous injection. Experimental animals were observed and sudden deaths during the experimental period were noted. The ED50 was determined by the method of Probit.

Untreated rabbits were used as a control without administration of any test compound, but were all dead within minutes of arachidonic acid injection as a result of pulmonary embolism.

The results expressed as ED50 are given in Table 3 below.

In this table, the compounds of the invention are identified as in Experiment 1.

table 1

Test compound ED50 (mg / kg) • · 25 _ A 0.27 B 0.12

Datsoxibene 1.1 30 _

The results given above show about 5-6 times higher activity than the known compound Dazoxibene.

The above results indicate that the compounds of the invention inhibit thromboxane synthetase in mammalian, including human, platelet microsomes and that they further show a potent and

II

107 95252 specific inhibitory activity against TXA2 biosynthesis. Specifically, TXA2 biosynthesis can be inhibited up to 50% by a molar concentration of the compound of the order of 10'8. However, the compounds of the present invention have a very weak inhibitory effect against cyclooxygenase and prostacyclin synthetase and thus do not inhibit the synthesis of other prostaglandin derivatives.

Claims (4)

95252 A process for the preparation of dihydro-5-thianaphthalene compounds of formula (I) useful as medicaments: wherein: one of A1 and A2 represents a group of formula -ZY, wherein Y represents an imidazolyl or pyridyl group and Z represents a methylene, ethylene- , a trimethylene or vinylene group or a methylene, ethylene, trimethylene or vinylene group having at least one substituent selected from the group consisting of C1-C6 alkyl groups, C3-C6 cycloalkyl groups, phenyl or naphthyl groups, substituted phenyl groups, there is at least one substituent selected from the group consisting of C 1 -C 3 alkyl groups, C 1 -C 3 alkoxy groups, halogen atoms, nitro * groups, cyano groups and amino groups; and thienyl groups; one of A1 and A2 represents a group of the formula -W-C00H, wherein W represents a direct bond, a methylene group, a methine group, provided that W represents only said methine group when A1 represents said group of the formula -Z-Y; A2 is in the 5- or 6-position of the thianaphthene system; each dashed line represents a single or double carbon-35 carbon bond between the 4- and 5- or 6- and 7-positions, provided that when A2 is in the 5-position there is a single bond between the 6- and 7-positions and that when A2 is in the 6-position There is a simple bond between the 4- and 5-positions; n 95252 and pharmaceutically acceptable salts, amides and esters thereof, characterized in that a compound of formula (II) is administered: wherein the dashed lines are as defined above; one of B1 and B2 represents Ax: a group -WCOOH represented by n or A2 or a group in which the carboxy group is protected, and one of B1 and B2 represents a reactive group such as hydroxy, halogen, lower alkanesulfonyloxy or arylsulfonyloxy or is a carbonyl derivative of Z wherein Z is as defined above) react with an imidazolyl or pyridyl compound to introduce an imidazolyl or pyridyl group represented by Y into said compound and, if necessary, subjecting the resulting compound to reduction and / or hydrolysis and / or deprotection, and if desired the salts are prepared in known ways, preferably by contacting a suitable acid or base with each other. Process according to Claim 1, characterized in that the reagents and reaction conditions are chosen from 4,5,6,7-tetrahydro-2- (1-imidazolyl) methyl ianaphthene-6-carboxylic acid or a pharmaceutically acceptable salt thereof. , to prepare an ester or amide. Process according to Claim 1, characterized in that the reagents and reaction conditions are chosen for the preparation of 4,5-dihydro-2- (1-imidazolyl) methylthianaphthene-6-carboxylic acid 95252 or a pharmaceutically acceptable salt, ester or amide thereof. Process according to Claim 1, characterized in that the reagents and reaction conditions are chosen from 4,5,6,7-tetrahydro-2- (1-imidazolyl) methylthianaphthene-5-carboxylic acid or a pharmaceutically acceptable salt thereof, ester or to prepare an amide. 10 li 95252